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Department of Human Anatomy and Histology, School of Medicine, University of Bari, Bari, Italy (D.R.); Departments of Pharmaceutical Sciences, School of Pharmacy (M.T.C.) and Human Anatomy and Physiology (G.G.N.), School of Medicine, University of Padua, Padua, Italy
Abstract I. Introduction II. Classic Mechanisms of Angiogenesis Regulation A. General Overview B. The Angiogenic Switch 1. Genetic Factors. 2. Secretion of Growth Factors. 3. Recruitment of Inflammatory Cells Releasing Angiogenic Factors. 4. Mobilization of Angiogenic Cytokines from Extracellular Matrix. 5. Interactions of Adhesion Receptors with Matrix Metalloproteinase-2. 6. Classic Endogenous Inhibitors of Angiogenesis (Table 1). 7. The Validity of in Vitro and in Vivo Assays as Predictors of Effects on Angiogenesis Relevant to Physiology and Pathophysiology. C. Tumor Angiogenesis III. Nonclassic Endogenous Stimulators of Angiogenesis A. Erythropoietin B. Angiotensin II C. Endothelins D. Proadrenomedullin-Derived Peptides 1. Adrenomedullin. 2. Proadrenomedullin N-Terminal 20 Peptide. E. Urotensin-II F. Adipokines 1. Leptin. 2. Adiponectin. 3. Resistin. G. Neuropeptide-Y H. Vasoactive Intestinal Peptide and Pituitary Adenylate Cyclase-Activating Polypeptide I. Substance P J. Summary IV. Nonclassic Endogenous Inhibitors of Angiogenesis A. Somatostatin B. Ghrelin C. Natriuretic Peptides D. Summary V. Conclusions and Perspectives
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I. Introduction |
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). Angiogenesis is regulated, under both physiological and pathological conditions, by numerous "classic" factors, among which are vascular endothelial growth factor (VEGF1), fibroblast growth factor-2 (FGF-2), transforming growth factors (TGFs), angiopoietins, platelet-derived growth factor (PDGF), thrombospondin-1, and angiostatin. Several excellent reviews on this topic are available (Cross and Claesson-Welsh, 2001; Ribatti et al., 2002b; Suhardja and Hoffman, 2003; Turner et al., 2003; Ferrara, 2004; Hoeben et al., 2004; Simons, 2004; Tait and Jones, 2004; Presta et al., 2005; D'Andrea et al., 2006; Folkman, 2006; Ren et al., 2006; Rüegg et al., 2006).
In recent years, evidence has accumulated that, in addition to the classic factors, many other endogenous peptides play an important regulatory role in angiogenesis, especially under pathological conditions. Although some articles surveyed the angiogenic regulatory action of some of these peptides (see sections III. and IV.), a comprehensive review of the "nonclassic" angiogenesis regulators has not yet been published. Thus, after a brief account of the classic angiogenetic mechanisms, we will survey the role played by the nonclassic proangiogenic and antiangiogenic endogenous peptides under physiological and pathological conditions, as well as their possible signaling mechanism(s) and their interaction(s) with the classic angiogenic factors. Finally, the new possible therapeutic perspectives opened by investigations of nonclassic angiogenic mechanisms will be discussed shortly.
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II. Classic Mechanisms of Angiogenesis Regulation |
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Angiogenesis, a term applied to the formation of capillaries from preexisting vessels, i.e., capillary and postcapillary venules, is based on endothelial sprouting or intussusceptive (nonsprouting) microvascular growth (Risau, 1997). The latter represents an additional and/or alternative mechanism and is not dependent on local endothelial cell (EC) proliferation or sprouting: a large sinusoidal capillary divides into smaller capillaries, which then grow separately (Djonov et al., 2000).
Sprouting angiogenesis is a multistep, highly orchestrated process, which involves not only vessel sprouting, but also cell migration, proliferation, tube formation, and survival (Risau, 1997). It develops through five steps: 1) basement membrane degradation by the action of proteolytic enzymes, such as matrix metalloproteinases (MMPs) and plasminogen activators secreted by ECs, resulting in the formation of tiny sprouts penetrating the perivascular stroma; 2) migration of the ECs at the sprout tip toward the angiogenic stimulus; 3) proliferation of the ECs below the sprout; 4) canalization, branching, and formation of vascular loops, leading to the development of a functioning circulatory network; and 5) perivascular apposition of pericytes and vascular smooth muscle cells (VSMCs) to support the abluminal side and de novo synthesis by ECs and pericytes of the basement membrane constituents.
As the vascular system develops, the initial plexus becomes remodeled into a complex and heterogeneous array of blood vessels, including larger vessels, such as arteries and veins (after forming a media and adventitia), and smaller vessels, such as venules, arterioles and capillaries (after association with pericytes). Differentiation of arteries and veins was thought to be exclusively governed by hemodynamic forces, molding these vessels from the primary vascular plexus. However, the discovery that members of the ephrin family are differentially expressed in arteries and veins from very early stages of development (i.e., before the development of functional circulation), was one of the first indications that arteryvein identity is intrinsically programmed: Ephrin-B2 marks arterial ECs and VSMCs, whereas ephrin-B4 marks veins (Wang et al., 1998).
Pericytes are adventitial cells located within the basement membrane of capillary and postcapillary venules. Because of their multiple cytoplasmic processes, distinctive cytoskeletal elements, and envelopment of ECs, pericytes are generally considered to be contractile cells that stabilize the vessel wall and participate in the regulation of microcircular blood flow (von Tell et al., 2006). They may also influence EC proliferation, survival, migration, and maturation (von Tell et al., 2006). The balance between the number of ECs and pericytes seems to be highly controlled. Potential regulators include soluble factors acting in an autocrine and/or paracrine manner, mechanical forces secondary to blood flow and blood pressure, and homotypic and heterotypic cell contacts. For example, PDGF is involved in EC to pericyte signaling, stimulating pericyte migration and proliferation (Lindahl et al., 1997). Moreover, pericytes may differentiate into VSMCs (Rhodin and Fujita, 1989). Targeted disruption of the PDGF-BB gene resulted in a defective development of the VSMCs (Levéen et al., 1994).
The vascular system is highly heterogeneous and nonuniform in different organs and tissues (Ribatti et al., 2002a). It is widely accepted that the organotypic differentiation of ECs is dependent on interactions with stromal parenchymal cells in target tissues. Heterogeneity develops partly through interactions of endothelium with the organ and tissue environment via either soluble factors or cell-cell interactions, leading to a particular phenotype of the endothelium. Interactions between different microvascular and surrounding tissue cells play a major role in determining vascular structure and function. These interactions may occur through the release of cytokines and the synthesis and organization of matrix proteins on which the endothelium adheres and grows. The organ microenvironment can directly contribute to the induction and maintenance of the angiogenic factors (Ribatti, 2006).
Angiogenesis is controlled by the balance between molecules that have positive and negative regulatory activity (Pepper, 1997). This concept led to the notion of the "angiogenic switch," which depends on an increased production of one or more positive regulators of angiogenesis (Ribatti et al., 2007). EC turnover in the healthy adult organism is low, the quiescence being maintained by the dominant influence of endogenous angiogenesis inhibitors over angiogenic stimuli. In pathological situations angiogenesis may be triggered not only by the overproduction of proangiogenic factors, but also by the down-regulation of inhibitory factors. Various regulatory elements control the switch to the vascular phase.
1. Genetic Factors.
In transgenic mice containing an oncogene in the 
-cells of the pancreatic islets, angiogenic activity was observed in a subset of hyperplastic islet cells before the onset of tumor formation (Ribatti et al., 2007). In a tumor model of transgenic mice containing the genome of the bovine papilloma virus type I, the switch to the angiogenic phenotype was associated with the ability to export FGF-2 from the cells (Kandel et al., 1991). In cultured human fibroblasts, the angiogenic switch has been reported to be controlled by the tumor suppressor gene p53, which regulates the synthesis of thrombospondin-1 and is down-regulated during tumorigenesis (Dameron et al., 1994).
2. Secretion of Growth Factors.
Numerous inducers of angiogenesis have been identified (Table 1), among which FGF-2 and VEGF are the most potent. FGF-2 is a heparin-binding polypeptide that induces proliferation, migration, and protease production in cultured ECs and neovascularization in vivo (Basilico and Moscatelli, 1992). It interacts with ECs through tyrosine kinase-FGF receptors (Rs) and low-affinity, high-capacity heparan sulfate proteoglycan Rs on the cell surface and in the extracellular matrix (ECM) (Rusnati and Presta, 1996). However, FGF-2 genetically deficient mice possess a normal vasculature and apparently do not display defects related to impaired angiogenesis (Ortega et al., 1998).
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VEGF is an angiogenic factor in vitro and in vivo and a mitogen for ECs with effects on vascular permeability. It plays a role in the control of blood vessel development and pathological angiogenesis and is expressed when angiogenesis is high, and its levels are low when angiogenesis is absent (Ferrara, 2004; Hoeben et al., 2004; Ribatti, 2005). VEGF and VEGF Rs are the first EC-specific signal transduction pathway activated during vascular development and are critical molecules in the formation of the vascular system, as evidenced in embryos homozygous and heterozygous for a targeted null mutation in their genes (Ferrara et al., 2003). VEGF and its Rs function in a paracrine manner: VEGF expression is elevated in tissues of the developing embryo at the onset of their vascularization, and ingrowing vascular sprouts express high levels of VEGF Rs (Ferrara et al., 2003).
Other angiogenic factors involved in the switch are TGF-1, PDGF-B, and angiopoietins 1 and 2. When mesenchymal cells are treated with TGF-1, they express VSMC markers, indicating differentiation toward a VSMC lineage, and the differentiation can be blocked by antibodies against TGF-1 (Hirschi et al., 1998). TGF-1 has been also reported to direct neural crest cells toward a VSMC lineage (Shah et al., 1996). PDGF-B is secreted by ECs, presumably in response to VEGF and facilitates recruitment of mural cells. PDGF-B gene mutation may cause failure of pericyte recruitment (Lindhal et al., 1997). Angiopoietins 1 and 2 play a role in vascular stabilization. The former is associated with developing vessels and its absence leads to defects in vascular remodeling (Thurston, 2003); the latter antagonizes angiopoietin-1 action, causing destabilization of preexisting vessels. It is found in tissues such as ovary, uterus, and placenta that undergo transient or periodic growth and vascularization, followed by regression (Maisonpierre et al., 1997).
3. Recruitment of Inflammatory Cells Releasing Angiogenic Factors.
The stromal microenvironment is essential for cell proliferation and angiogenesis through its provision of survival signals, secretion of growth and proangiogenic factors, and direct adhesion molecule interactions. For example, tumor cells are surrounded by an infiltrate of inflammatory cells, namely lymphocytes, neutrophils, macrophages, and mast cells, which communicate via a complex network of intercellular signaling pathways mediated by surface adhesion molecules, cytokines, and their Rs. Evidence is accumulating that mast cells play an important role in angiogenesis: FGF-2, VEGF, and PDGF stimulate migration of mast cells that produce tryptase, which in turn degrades ECM to provide space for neovascular sprouts (Feoktistov et al., 2003; Hiromatsu and Toda, 2003). In this connection, it seems of interest to recall that findings indicate that mast cells were found to express and release angiogenic regulatory peptides, such as endothelin (ET)-1 (Maurer et al., 2004; Hültner and Ehrenreich, 2005) and adrenomedullin (AM) (Belloni et al., 2005, 2006; Tsuruda et al., 2006; Zudaire et al., 2006) (see sections III.C. and III.D.1.).
4. Mobilization of Angiogenic Cytokines from Extracellular Matrix.
FGF-2, VEGF, and TGF- are stored in the heparin-like glycosaminoglycans of ECM and may be released after ECM degradation by proteinases secreted by tumor and inflammatory cells (Mignatti and Rifkin, 1993). Tumor and inflammatory cells also secrete proteinase inhibitors, thereby making it likely that the degree of ECM degradation and ensuing angiogenesis stimulation by released cytokines depends on the level of proteinase/proteinase inhibitor equilibrium (Pepper et al., 1994).
5. Interactions of Adhesion Receptors with Matrix Metalloproteinase-2.
The adhesion receptor 
3 is selectively expressed on growing blood vessels (Brooks et al., 1994). 3 Integrin binds activated MMP-2 to the surface of ECs, facilitating ECM degradation (Brooks et al., 1996). Thus, the adhesion receptor 3 may act cooperatively with MMP-2 to promote EC functions necessary for angiogenesis, such as cell adhesion and migration (Li et al., 2003a; van Hinsbergh et al., 2006).
6. Classic Endogenous Inhibitors of Angiogenesis (Table 1).
Thrombospondin-1 was the first protein to be recognized as a naturally occurring inhibitor of angiogenesis (Good et al., 1990) (Table 1). It is a heparin-binding protein that is stored in ECM, is able to inhibit proliferation of ECs from different tissues (Taraboletti et al., 1990), and destabilizes contacts among ECs (Iruela-Arispe et al., 1991). Tumors grow significantly faster in thrombospondin-1-null mice than in wild-type animals (Lawler, 2002).
Angiostatin has been identified as a 38-kDa internal fragment identical in amino acid sequence to the first four kringle structures of plasminogen (O'Reilly et al., 1994). Angiostatin inhibits growth of primary tumors by up to 98% and is able to induce regression of large tumors and to maintain them at a microscopic dormant size (O'Reilly et al., 1996).
Endostatin isolated by O'Reilly et al. (1997) is the 20 kDa C-terminal proteolytic fragment of the basement membrane component collagen XVIII. Endostatin has been proposed to interfere with VEGF and FGF-2 pathways (Taddei et al., 1999; Yamaguchi et al., 1999), to induce EC apoptosis (Dhanabal et al., 1999), and to inhibit MMP (Kim et al., 2000).
7. The Validity of in Vitro and in Vivo Assays as Predictors of Effects on Angiogenesis Relevant to Physiology and Pathophysiology. One of the major problems in angiogenesis research is the difficulty of finding suitable methods for assessing the angiogenic response. A single assay that is optimal for all situations has not yet been described, and ideally it should be easy, reproducible, quantitative, and cost-effective and should permit rapid analysis. To full understand and interpret the effects of a particular test substance on the process of angiogenesis, it is necessary to use more than one in vitro assay and to use different sources of ECs. Only this procedure can ensure that the results seen in vitro translate across to the in vivo conditions, where other cells and ECM proteins are involved in the process of angiogenesis.
It is generally accepted that tumor growth is angiogenesis-dependent and that any increment of tumor growth requires an increase in vascular growth (Ribatti et al., 1999b). Tumor angiogenesis is an uncontrolled and unlimited process essential for tumor growth, invasion, and metastasis, which is regulated by the interactions of numerous mediators and cytokines with pro- and antiangiogenic activity. Tumors lacking angiogenesis remain dormant indefinitely.
New vessels promote growth by conveying oxygen and nutrients and removing catabolites, whereas ECs secrete growth factors for tumor cells and a variety of ECM-degrading proteinases that facilitate invasion. An expanding endothelial surface also gives tumor cells more opportunities to enter the circulation and metastasize, whereas their ability to release antiangiogenic factors may explain the control exerted by primary tumors over metastasis. Growth of solid and hematological tumors consists of an initial avascular and a subsequent vascular phase (Ribatti et al., 1999b, 2004; Vacca and Ribatti, 2006). Assuming that the latter process is dependent on the angiogenesis and the release of angiogenic factors, the acquisition of angiogenic capability can be seen as an expression of progression from neoplastic transformation to tumor growth and metastasis.
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III. Nonclassic Endogenous Stimulators of Angiogenesis |
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Erythropoietin (EPO) is a 30.4-kDa glycoprotein, which plays a crucial role in the maintenance and stimulation of erythropoiesis and erythrocyte differentiation. EPO is produced from peritubular fibroblast-like cells of the kidney cortex after birth and during the fetal life from hepatocytes. Its gene expression is induced by hypoxia-inducible transcription factors (HIFs). EPO acts via two R molecules that mainly activate Janus kinase (JAK)/signal transducer and activator of transcription (STAT) and phosphatidylinositol 3-kinase (PI3K)/Akt pathways. Evidence has accumulated that EPO also exerts a marked proangiogenic effect during embryonic and adult life, as well as enhances tumor growth by promoting angiogenesis and decreasing apoptosis (Ghezzi and Brines, 2004; Jelkmann, 2004; Koury, 2005; Rossert and Eckardt, 2005; Hardee et al., 2006). Administration of recombinant human EPO to patients with head and neck and breast cancers expressing EPO Rs may promote tumor growth via the induction of cell proliferation and angiogenesis (Henke et al., 2003; Leyland-Jones, 2003). Nevertheless, several preclinical studies have shown a beneficial effect of EPO on delaying tumor growth through reduction of tumor hypoxia and the deleterious effects of hypoxia on tumor growth, metastasis, and treatment resistance (Farrell and Lee, 2004), and a meta-analysis did not find an unfavorable effect on overall survival of the treated cancer patients (Bohlius et al., 2005). However, it is important to underline a strong-enough caution on the use of EPO in patients with malignancies, according to the directive of the US Food and Drug Administration.
EPO R mRNA expression was detected in human ECs (Anagnostou et al., 1994). EPO was found to stimulate proliferation and migration of cultured mature ECs and to lower the apoptotic rate (Anagnostou et al., 1990; Dimmeler and Zeiher, 2000; Jaquet et al., 2002; Ribatti et al., 2003b). The same effects were reported in cultured neonatal ECs, in which EPO also induced capillary-like tube formation (Ashley et al., 2002), and in embryonic ECs, in which EPO promoted differentiation into the mature phenotype (Heeschen et al., 2003; Müller-Ehmsen et al., 2006). Evidence has been provided that these effects were mediated by the EPO R-mediated activation of JAK/STAT and PI3K/Akt pathways (Haller et al., 1996; Ribatti et al., 1999a; Dimmeler and Zeiher, 2000; Mahmud et al., 2002). The proangiogenic effect of EPO has been confirmed in vivo in the chick embryo chorioallantoic membrane (CAM) assay (Ribatti et al., 1999a, 2003b), and in experimental models of myocardium and hind limb ischemia (Calvillo et al., 2003; Heeschen et al., 2003; Parsa et al., 2003).
The angiogenic potential of EPO has been reported to be similar to that of FGF-2 (Ribatti et al., 1999a) and VEGF (Jaquet et al., 2002). Of interest, findings suggested that EPO could stimulate angiogenesis in vitro through an autocrine mechanism involving the proangiogenic peptide ET-1 (see section III.C.): EPO enhanced ET-1 release from ECs, and its angiogenic effect was blunted by an anti-ET-1 antibody (Carlini et al., 1993, 1995).
Angiotensin (ANG) II is a well-known octapeptide hormone that regulates blood pressure, plasma volume, and electrolyte balance mainly through its stimulating action on aldosterone and vasopressin release, cardiovascular tissue growth, and neuronal sympathetic activity. It is the active component of the classic renal renin-angiotensin system, for which circulating kidney-derived renin cleaves liver-derived angiotensinogen to the decapeptide ANG-I, that in turn is transformed, mainly in the lung, by angiotensin-converting enzyme (ACE) to ANG-II. ANG-II may also be produced locally by several tissue renin-angiotensin systems. ANG-II acts through two main subtypes of G protein-coupled receptors (GPRs), referred to as AT1-R and AT2-R, that both are abundantly expressed in the vasculature (Matsusaka and Ichikawa, 1997; Touyz and Schiffrin, 2000).
ANG-II was found to be angiogenic in vivo in the CAM and in the rabbit cornea assay (Fernandez et al., 1985; Le Noble et al., 1991), and the bulk of the findings indicated that this effect was mediated by the AT1-R, with AT2-R playing an opposite action which was overcome by AT1-R activation. ANG-II was shown to stimulate the growth of quiescent ECs via AT1-Rs, but in the presence of proangiogenic factors it dampened EC growth via AT2-Rs (Stoll et al., 1995). The AT2-R blockade enhanced the angiogenic effect of ANG-II in rat subcutaneous sponge granuloma (Walsh et al., 1997). Sasaki et al. (2002) provided evidence that AT1-Rs could play an important role in ischemia-induced angiogenesis. Well-developed collateral vessels and neoangiogenesis were observed in wild-type mice in response to hind limb ischemia, whereas the response was markedly reduced in AT1-R KO mice. Ischemia-induced angiogenesis was also impaired in wild-type mice by AT1-R blockade by a selective antagonist. Moreover, the suppression of inflammatory cell infiltration by the AT1-R blockade could provide an unique strategy against angiogenic disorders, including malignant tumors. In fact, infiltration of macrophages and T lymphocytes promote tumor related-angiogenesis (Balkwill and Mantovani, 2001).
Silvestre et al. (2002) reported that the ischemic/nonischemic hind limb angiographic ratio and blood flow were markedly higher in AT2-R KO mice compared with wild-type animals. ANG-II was found to be cosecreted with ET-1 by ECs, suggesting its possible autocrine/paracrine mechanism of action (Kusaka et al., 2000).
ANG-II was shown to induce VEGF expression in VSMCs, which may stimulate EC proliferation, migration, and angiogenesis (Williams et al., 1995; Chua et al., 1998; Otani et al., 1998; Richard et al., 2000). The VEGF involvement in the AT1-R-mediated angiogenic response of ischemic tissues has been demonstrated. The infiltration of inflammatory mononuclear cells, including macrophages and T cells, was suppressed in the ischemic hind limb of AT1-R KO mice. Double immunofluorescence staining revealed that infiltrated inflammatory cells expressed VEGF, and the expression of VEGF and monocyte chemoattractant protein-1 was also decreased in KO mice (Sasaki et al., 2002). VEGF-mediated angiogenesis was impaired by AT1-R blockade in the cardiomyopathic hamster heart, because this procedure markedly lowered VEGF mRNA expression, and capillary and microvascular density (Shimizu et al., 2003). No differences in VEGF protein expression were observed in the ischemic hind limb of wild-type and AT2-R KO mice, and ANG-II increased it in both strains. Of interest, endothelial nitric-oxide synthase (NOS) protein levels were higher in AT2-R KO mice than in the wild type controls, indicating that AT2-R down-regulated NO production (Silvestre et al., 2002). These last investigators also provided evidence that the antiangiogenic effect of AT2-Rs was connected with the activation of apoptotic process in vascular cells.
Sporadic findings have been obtained, suggesting an antiangiogenic effect of endogenous ANG-II. In fact, in a rabbit model of hind limb ischemia the blockade of ANG-II production induced by the treatment with the ACE inhibitor enalapril led to an increase of angiogenesis (Fabre et al., 1999). Accordingly, in nude mice inoculated with alginate beads encapsulating human and mouse carcinoma-derived cell lines, the daily administration of enalapril induced a marked increase of angiogenesis within 11 days (Walther et al., 2003). However, these investigators observed that in transgenic mice overexpressing ANG-II, the angiogenic response in alginate bead implants was markedly increased, the response being abolished by the AT2-R antagonist PD123319 and unaffected by the AT1-R antagonist losartan. In keeping with this finding, the angiogenic response of implants was reduced in AT2-R KO mice. In light of these findings, Walther et al. (2003) advanced the "unorthodox" hypothesis that ANG-II regulates in vivo angiogenesis acting through both AT1-Rs and AT2-Rs, which exert an inhibitory and a stimulatory effect, respectively.
ETs are a family of hypertensive 21-amino acid peptides, mainly secreted by ECs. This family includes three distinct isoforms, named ET-1, ET-2, and ET-3, which derive by the post-translational cleavage of inactive precursors, the big-ETs, by specific endopeptidases, referred to as endothelin-converting enzymes. ETs act via two main classes of GPRs, named ETA-Rs and ETB-Rs, whose potency in binding ETs is as follows: ETA-R, ET-1 = ET-2
; Nussdorfer et al., 1999; Davenport, 2002). ETs and their receptors are present in a variety of tissues, where they play important physiological and pathophysiological roles, mainly concerning cardiovascular system (Kedzierski and Yanagisawa, 2001; Rossi et al., 2001; D'Orléans-Juste et al., 2002).
Human umbilical vein ECs (HUVECs) were found to express high levels of ET-1 and ETB-R mRNAs and low levels of ETA-R mRNA (Salani et al., 2000b; Bagnato et al., 2001). These cells also actively produced and secreted ET-1 (Fujitani et al., 1992; Flynn et al., 1998). Secretion of costored ANG-II and ET-1 by coronary rat ECs was also reported, and the process was inhibited by NO and enhanced by NOS inhibition (Kusada et al., 2000). Evidence has also been provided that ECM regulated ET-1 secretion by HUVECs: collagen IV dampened ET-1 secretion, whereas collagen I, acting via the activation of integrin and tyrosine kinase, stimulated it (González-Santiago et al., 2002). A potential autocrine role for endogenous ET-1 has also been suggested, inasmuch as ET-1 via the ETB-R was shown to increase its own synthesis (Saijonmaa et al., 1992).
ET-1 and ET-3, acting via the ETB-R, promoted in vitro EC proliferation (Vigne et al., 1990; Morbidelli et al., 1995; Noiri et al., 1997, 1998; Goligorsky et al., 1999) and migration (Ziche et al., 1990; Noiri et al., 1997). HUVECs cultured on Matrigel in the presence of ET-1 migrated throughout and aligned to form capillary-like tubular structures, and the effect was inhibited by the selective ETB-R antagonist BQ788, but only weakly impaired by the ETA-R antagonist BQ123, thereby confirming the main involvement of the ETB-R in the angiogenic action of ET-1 (Salani et al., 2000b). Recent findings indicated that ET-1 stimulated HUVEC proliferation via ETB-Rs coupled to Ca2+-activated large conductance potassium channels, whose activation induced hyperpolarization of the cell membrane and consequently raised Ca2+ influx (Kuhlmann et al., 2005). ET-1 was found to act as an antiapoptotic factor for ECs and VSMCs, thus contributing to the maintenance of the integrity of newly formed blood vessels (Shichiri et al., 1997, 2000; Wu-Wong et al., 1997).
The most striking angiogenic effect was seen when ET-1 was combined with VEGF. Whereas unable to stimulate blood vessel growth in the chick embryo CAM (Ribatti et al., 1999a) and in a rat sponge model (Hu et al., 1996), ET-1, in association with VEGF, showed clear proangiogenic activity in the Matrigel plug implanted into mice (Salani et al., 2000b). ET-1-producing Chinese hamster ovary cells grafted onto CAM induced a clearcut angiogenic effect, which was prevented by the mixed ETA/ETB-R antagonist bosentan and the endothelin-converting enzyme-1 inhibitor phosphoramidon. Chinese hamster ovary/ET-1-mediated effect was also prevented by an inhibitor of VEGF tyrosine kinase Rs, thereby confirming the involvement of VEGF in the ET-1 angiogenic response (Cruz et al., 2001). VEGF increased both the expression of ET-1 mRNA in and ET-1 secretion from ECs (Matsuura et al., 1998). ET-1, acting predominantly via the ETA-R, stimulated both the expression of VEGF mRNA in and VEGF secretion from VSMCs, as well as enhanced VEGF-induced EC proliferation and migration (Pedram et al., 1997a,b; Okuda et al., 1998). Thus, VEGF and ET-1 have reciprocal stimulatory interactions, which may result in concomitant proliferation of ECs and VSMCs.
In cancer, VEGF and ET-1 have been reported to be up-regulated by various stimuli, including hypoxia, growth factors, and inflammatory cytokines (Okuda et al., 1998; Molet et al., 2000; Yamashita, 2001). Overexpression of ET-1 and its Rs was found in lung cancer, Kaposi's sarcoma, colon cancer, astrocytomas, and glioblastomas (Stiles et al., 1997; Ahmed et al., 2000; Egidy et al., 2000a,b; Asham et al., 2001; Bagnato et al., 2001; Fagan et al., 2001; Bagnato and Spinella, 2003). ABT-627, a potent ET antagonist (Verhaar et al., 2000), displayed antitumor activity and decreased neovascularization in vivo against established ovarian cancer xenografts in nude mice (Rosanò et al., 2001).
ET-1/VEGF interactions have been demonstrated to occur also in tumors. In primary and metastatic ovarian carcinomas, there was a highly significant correlation between ET-1 expression and microvascular density, as well as between ET-1 and VEGF expression (Salani et al., 2000a). The high amount of ET-1 released by ovarian carcinoma cells into ascitic fluid was responsible primarily for EC migration, acting via the ETB-R, as demonstrated by its inhibition by BQ788. The significant inhibition of migration observed by coincubating HUVECs with BQ788 and anti-VEGF antibodies suggested that ET-1 and VEGF might have a complementary and coordinated role during neovascularization in ovarian carcinoma (Salani et al., 2000a). When tested in ovarian carcinoma-derived cell lines, ET-1 increased VEGF mRNA expression and induced VEGF production in a time- and dose-dependent fashion and did so to a greater extent during hypoxia (Salani et al., 2000a; Spinella et al., 2002). There is also evidence that ET-1 promoted VEGF production through HIF-1: after ET-1 stimulation, the HIF-1 protein level increased in ovarian carcinoma cells, and the HIF-1 transcription complex was formed and bound to the hypoxia-responsive element-binding site (Spinella et al., 2002). These actions of ET-1 were mediated by the ETA-R, because BQ123 reversed the stimulation of VEGF production (Spinella et al., 2002). ET-1-induced ETA-R activation stimulated prostaglandin-E2 (PGE2) production and increased the expression of PGE2 R type 2 and type 4. Cyclooxygenase-1 and -2 inhibitors blocked ET-1-induced PGE2 and VEGF release by ovarian carcinoma cells. Thus, the conclusion was drawn that PGE2 contributed to the tumor progression by promoting angiogenesis and that this effect was mediated by VEGF (Spinella et al., 2004).
D. Proadrenomedullin-Derived Peptides
AM and proadrenomedullin N-terminal 20 peptide (PAMP) are produced by the post-translational proteolytic cleavage of a 185-amino acid prohormone, the pre-pro-AM. AM (a 52-amino acid peptide in humans) and PAMP exert potent long-lasting and transient hypotensive effects, respectively. Although originally isolated from human pheochromocytomas, AM and PAMP have been subsequently shown to be synthesized in several tissues and organs, including blood vessels and heart. AM acts via selective Rs derived from the calcitonin receptor-like receptor (CRLR), which may act as either a calcitonin gene-related peptide (CGRP) or an AM R, depending on its interactions with the members of a family of single transmembrane domain proteins, named receptor-activity-modifying proteins (RAMPs): RAMP1 generates CGRP Rs from CRLRs, whereas RAMP2 and RAMP3 produce AM Rs, called AM1-R and AM2-R, respectively. CGRP(8–37) and AM(22–52) have been identified as AM1-R and AM2-R antagonists (Hinson et al., 2000; López and Martínez, 2002; Poyner et al., 2002; Julián et al., 2005; García et al., 2006). PAMP binding sites are well distinct from AM Rs but have not yet been fully characterized, although recent findings seem to suggest that corticostatin MrgX2-R may act as PAMP R (Kamohara et al., 2005; Nothacker et al., 2005). Nevertheless, evidence indicates that PAMP(12–20) behaves as a potent antagonist of PAMP Rs (Belloni et al., 1999).
1. Adrenomedullin.
AM exerts several biological actions, including regulation of fluid and electrolyte homeostasis (Samson, 1999; Nussdorfer, 2001) and protective action on the cardiovascular system (Kato et al., 2005). Moreover, evidence that AM possesses a clearcut proangiogenic effect under both physiological and pathophysiological conditions has accumulated, and reviews on this topic have already been published (Nikitenko et al., 2002, 2006; Nagaya et al., 2005; Ribatti et al., 2005).
A genetically determined absence of AM may be one of the causes of nonimmune hydrops fetalis and hemorrhage, as a result of cardiovascular abnormalities and disturbance of angiogenesis and lymphangiogenesis (Caron and Smithies, 2001; Shindo et al., 2001). AM has been reported to exert its angiogenic activity via AM1-Rs and AM2-Rs, which activate mitogen-activated protein kinase (MAPK) and Akt cascades and focal adhesion kinase (Kim et al., 2003b; Miyashita et al., 2003; Fernandez-Sauze et al., 2004), as well as play an anti-inflammatory role in controlling VEGF-induced adhesion molecule gene expression and adhesiveness toward leukocytes in ECs (Kim et al., 2003a). AM augmented vascular collateral development in response to acute ischemia (Abe et al., 2003, 2006; Iwase et al., 2005) and enhanced capillary-like tube formation by HUVECs cultured on Matrigel and blood vessel formation in the CAM assay, the effect being counteracted by AM(22–52) (Ribatti et al., 2003a). AM gene transfer was found to induce therapeutic angiogenesis in a rabbit model of chronic hind limb ischemia (Tokunaga et al., 2004). Miyashita et al. (2006) and Xia et al. (2006) showed that AM administration improved vascular regeneration in the ischemic rat brain. Using immortalized human microvascular ECs, Schwarz et al. (2006) showed that AM increased cAMP production, stimulated MAPK p42/p44, and enhanced EC migration but not proliferation, all these effects being inhibited by AM(22–52). Moreover, AM raised the expression of both CRLR and RAMP2 mRNAs, suggesting up-regulation of AM1-Rs. The role of this receptor subtype in the mediation of the AM proangiogenic effect has been confirmed by the demonstration that RAMP2 gene silencing by short-interfering-RNA technology impaired the ability of HUVECs cultured on Matrigel to form capillary-like tubules in response to AM (Albertin et al., 2006).
Evidence has been provided that AM up-regulated the expression of VEGF in both in vitro and in vivo models (Iimuro et al., 2004; Albertin et al., 2005; Schwarz et al., 2006). Using laser Doppler perfusion imaging, Iimuro et al. (2004) showed that AM stimulated recovery of blood flow to the affected limb in a mouse hind limb ischemia model, partly by promoting local expression of VEGF. Immunostaining for the EC marker CD31 revealed that this enhanced flow reflected increased capillary density. In EC and fibroblast cocultures, AM raised VEGF-induced capillary formation, and in EC cultures it increased VEGF-induced Akt activation. Iimuro et al. (2004) also demonstrated that heterozygous AM KO mice treated with AM(22–52) displayed reduced capillary development, and the administration of either AM or VEGF favored blood flow recovery and capillary formation. However, blocking antibodies to VEGF did not significantly inhibit AM-induced in vitro capillary-like tube formation by ECs (Fernandez-Sauze et al., 2004), suggesting that AM does not act directly through up-regulation of VEGF.
The detection of high levels of AM expression in various types of cancer cells suggests that this peptide is involved in tumor growth (Forneris et al., 2001; Li et al., 2001; Oehler et al., 2001; Martínez et al., 2002; Jimenez et al., 2003; Mazzocchi et al., 2004; Zudaire et al., 2006). In addition, AM expression and AM Rs have been detected in several carcinoma-derived cell lines (Hata et al., 2000; Belloni et al., 2001). AM produced by tumor cells is thought to inhibit their hypoxic death as an antiapoptotic factor (Oehler et al., 2001; Abasolo et al., 2006). AM was found to be up-regulated by hypoxia (Cormier-Regards et al., 1998; Nakayama et al., 1998), through the HIF-1 (Nguyen and Claycomb, 1999; Garayoa et al., 2000; Frede et al., 2005). Oehler et al. (2001) studied the role of AM in endometrial carcinoma cells under hypoxia and found that AM conferred resistance to hypoxic cell death in an autocrine/paracrine manner, the antiapoptotic effect being probably mediated by the up-regulation of the Bcl-2 oncogene.
AM overexpressing tumors are characterized by increased vascularity (Oehler et al., 2002, 2003), and an increased expression of AM mRNA in ovarian tumors has been statistically associated with a poor prognosis (Hata et al., 2000). Martínez et al. (2002) stably transfected human breast cancer-derived cell lines expressing low basal levels of AM, with an expression construct that contained the coding region of human AM gene or with an empty expression vector. Cells overexpressing AM displayed a more heterogenous morphology and increased angiogenic potential both in vitro and in vivo compared with those transfected with the empty vector. AM and VEGF have been reported to be the most widely expressed angiogenic factors in uterine leiomyomas (Hague et al., 2000). Leiomyomas displayed a higher vascular density and EC proliferative activity than normal myometrium and endometrium, and the expression of AM, but not of VEGF, correlated with the vascular density in these tumors.
Ribatti et al. (2003a) demonstrated that vinblastine was angiostatic in the angiogenic response induced by AM in two assays, namely capillary-like tube formation by HUVECs cultured on Matrigel and in vivo CAM vasculogenesis. They suggested that these findings implicate AM as a promoter of tumor growth and a possible target for anticancer strategies, such as the use of vinblastine at very low, nontoxic doses.
2. Proadrenomedullin N-Terminal 20 Peptide.
In vivo and in vitro angiogenic assays showed that PAMP was more effective than AM and VEGF, inasmuch as PAMP acted at femtomolar concentrations and these latter peptides only in the nanomolar range. Some differences were observed in the actions of AM and PAMP (Martínez et al., 2004, 2006). In in vitro assays with human dermal microvascular ECs, PAMP did not affect cell growth, whereas AM and VEGF enhanced it. PAMP and VEGF, but not AM, stimulated EC migration. Finally, PAMP was less effective than AM and VEGF in inducing tubular organization in Matrigel cultured ECs. PAMP lowered by approximately 50% Ca2+ influx induced by ATP, and the effect was reversed by PAMP(12–20). PAMP increased VEGF, FGF-2, and PDGF mRNA expression in ECs, as revealed by real-time PCR. In in vivo assays with silicon tubes filled with Matrigel implanted in mice, the PAMP-R antagonist PAMP(12–20) completely blocked angiogenesis induced by PAMP or human lung cancer-derived cell line. Moreover, PAMP(12–20) lowered tumor growth rate in xenograft-implant experiment with this cell line, whereas PAMP was ineffective. According to Martínez et al. (2004), this last finding could be due to a rapid cleavage of PAMP by tumor cells, which saturates PAMP Rs on ECs. It is concluded that PAMP is a potent proangiogenic factor and tumor growth promoter, which may act either directly on ECs or indirectly by inducing the production of classic angiogenic promoters. The PAMP-R antagonist PAMP(12–20) could be used in antineoplastic therapeutic strategies.
Urotensin-II is a cyclic 11-amino acid (human) or 15-amino acid (rodents) peptide, originally isolated from the fish urophysis, which exerts a potent systemic vaso-constrictor and hypertensive effect. Urotensin-II has been identified as an endogenous ligand of the orphan GPR-14, which has been renamed urotensin R (UT-R) (Ames et al., 1999; Davenport and Maguire, 2000). Urotensin-II and UT-R are widely expressed in the heart and large arteries, and many lines of evidence led to the conclusion that urotensin-II plays a role in the physiology and pathophysiology of cardiovascular system (Douglas and Ohlstein, 2000). Urotensin-II has also been shown to exert a marked mitogenic action on many cell phenotypes, and the expression of urotensin-II and UT-R has been detected in several tumor-derived cell lines (Yoshimoto et al., 2004). A UT-R antagonist has been identified and named palosuran (ACT058362) (Clozel et al., 2004).
Rat neuromicrovascular ECs were found to express urotensin-II and UT-R mRNAs and proteins, as revealed by PCR and immunocytochemistry. FGF-2 raised the EC proliferation rate, whereas urotensin-II did not. However, urotensin-II markedly stimulated the formation of capillary-like tubes by ECs cultured on Matrigel, and image analysis showed that the effect of this peptide was of the same order of magnitude as that of FGF-2. Accordingly, urotensin-II, added to CAM, induced a strong angiogenic response. Both in vitro and in vivo proangiogenic effects of urotensin-II were counteracted by Palosuran, indicating that it was mediated by the UT-R (Spinazzi et al., 2006).
The development of the vascular bed in adipose tissue is tightly connected to both the number and size of adipocytes, and adipose tissue serves as an important conduit for growing blood vessels. Immortalized preadipocyte cell lines were found to promote the formation of highly vascularized fat pads after injection into nude mice (Green and Kehinde, 1979), and adipocytes are known to secrete several cytokines, such as VEGF and tumor necrosis factor- (Zhang et al., 1997). Hence, it is conceivable that adipocytes may modulate the growth of the vasculature in a paracrine manner (Mohamed-Ali et al., 1998). In addition to secreting the above-mentioned classic proangiogenic cytokines, adipocytes produce three other regulatory peptides, the adipokines leptin, adiponectin and resistin, which seem to be involved in angiogenesis modulation under both physiological and pathological conditions.
1. Leptin.
Leptin, a 167-amino acid peptide in humans, is the protein product of the ob gene transcription, that acts through specific Ob-Rs, of which several isoforms (from Ob-Ra to Ob-Rf) have been described. Leptin is an adipose tissue-secreted hormone, which is involved in the regulation of satiety, metabolic rate, and thermogenesis (Ahima and Flier, 2000; Sweeney, 2002). In situations of continuous adipose-tissue growth, it is documented that angiogenesis is present (Crandall et al., 1997). Because obesity in humans is associated with an elevation of leptin in the plasma and the adipose tissue, it is tempting to speculate that the leptin-mediated cross-talk between adipocytes and ECs promotes angiogenesis.
ECs have been reported to express functionally active Ob-Ra and Ob-Rb, which mediated their leptin-induced proliferation, through the activation of STAT-3 and extracellular signal-regulated kinases (ERK) 1/2. Leptin also induced angiogenesis in vivo in the CAM and in the rat cornea assays (Bouloumié et al., 1998; Sierra-Honigmann et al., 1998). Ribatti et al. (2001) confirmed that leptin was able to stimulate angiogenesis when applied onto the chick CAM and showed that the angiogenic response was similar to that obtained with FGF-2. The stimulating property of leptin was specific, as the exposure to anti-leptin antibodies significantly inhibited the angiogenic response. However, the application to CAM of anti-FGF-2 antibodies reduced by approximately 40% the angiogenic effect of leptin, indicating that the activation of endogenous FGF-2 at least in part mediated leptin action. Evidence has been provided that leptin-induced new blood vessels were fenestrated, playing a critical role in the maintenance and regulation of vascular fenestration in the adipose tissue. In fact, leptin caused a rapid vascular permeability response when administered intradermally, which might provide a mechanism by which the excess amount of leptin would be exported into the circulation (Cao et al., 2001). Leptin has been found to be produced at a high level also in the placenta, a highly angiogenic tissue, where it could increase the exchange of small molecules between the maternal circulation and the fetus by the induction and maintenance of vascular permeability (Masuzaki et al., 1997).
Rather contrasting findings were reported by Cohen et al. (2001), who demonstrated that leptin induced the expression of angiopoietin-2 in adipose tissue without concomitant increase in VEGF, thereby providing a strong angiostatic rather than angiogenic signal. They proposed that induction of angiopoietin-2 by leptin in adipocytes is one of the events leading to adipose tissue regression, because this induction coincided with initiation of apoptosis in adipose tissue ECs.
The possible effects of leptin on tumor angiogenesis have not been investigated. However, findings showed that leptin not only stimulated proliferation of a mouse mammary carcinoma-derived cell line both cultured in vitro and implanted in syngeneic mice, but also enhanced the expression of VEGF and VEGF-R2, via PI3K, JAK/STAT, and ERK1/2 signaling pathways (Gonzalez et al., 2006).
2. Adiponectin.
Adiponectin is an adipose tissue-derived peptide, which in humans exists in a full-length and a globular form (230- and 147-amino acid residues, respectively). The former represents almost all adiponectin in plasma, the latter being generated by the proteolytic cleavage of the C-terminal region of the full-length form. Two adiponectin Rs have been recently identified: adipoR1, the receptor for globular adiponectin, and adipoR2, the receptor for full-length adiponectin. Adiponectin is a regulator of energy homeostasis and plays a role in the obesity-induced insulin resistance and related complications (Wolf, 2003; Kadowaki and Yamauchi, 2005).
Adiponectin has been supposed to play a role in vascular remodeling: it was down-regulated in obesity-linked diseases, such as coronary artery disease in type 2 diabetes (Kumada et al., 2003), and its overexpression exerted an anti-inflammatory effect on the vasculature and reduced atherosclerotic lesions in a mouse model (Arita et al., 2002; Okamoto et al., 2002). Of interest, the anti-inflammatory and antiatherogenic action of adiponectin may be linked to its inhibitory effect on interleukin-8 expression in and release from ECs, an effect mediated by the inhibition of the tumor necrosis factor--induced nuclear factor-
B-dependent pathway through the activation of the cAMP-protein kinase (PK) A and PI3K-Akt cascades (Kobashi et al., 2005).
Adiponectin has been reported to activate adenosine monophosphate kinase in ECs, leading to enhanced in vivo angiogenesis in murine Matrigel plug and rabbit cornea assays and inhibition of caspase 3-mediated apoptosis in HUVECs cultured in vitro (Kobayashi et al., 2004; Ouchi et al., 2004). Adiponectin has also been found to play a role in the ischemia-induced angiogenesis: in the ischemic limb, as a result of the excision of the femoral artery and vein, the blood flow returned to 80% of that of the nonischemic limb at day 28 after surgery in wild-type mice, whereas the flow recovery was impaired in adiponectin KO animals. This proangiogenic action seemed to be mediated by the stimulation of AMP kinase-dependent signaling within the skeletal muscle of ischemic limb (Shibata et al., 2004).
Surprisingly, opposite findings have been obtained by Bråkenhielm et al. (2004). They showed that adiponectin inhibited EC migration and proliferation in vitro and neoangiogenesis in vivo in the CAM and cornea assays, as well as decreased angiogenesis and induced apoptosis in tumors, obtained by implanting T241 fibrosarcoma cells in mice. However, a cross-talk between adiponectin and FGF-2 has been suggested to occur in ECs of hepatocellular carcinoma, supporting tumor angiogenesis and growth (Adachi et al., 2006). In fact, FGF-2 was found to induce the expression of the proangiogenic cell adhesion molecule T-cadherin (Ivanov et al., 2004) in tumor but not in normal liver ECs, and T-cadherin is a R for adiponectin (Hug et al., 2004).
3. Resistin.
Resistin, an adipose tissue-produced peptide (92 amino acid residues in humans), belongs to a family of proteins found in the inflammatory zone, called FIZZ. Resistin links obesity to diabetes, and it is considered a predictive factor for coronary atherosclerosis (Steppan et al., 2001; Be
towski, 2003; Verma et al., 2003; Reilly et al., 2005).
Resistin has been reported to promote VSMC proliferation via the ERK1/2 and PI3K pathways (Calabro et al., 2004) and to stimulate in vitro angiogenesis (Mu et al., 2006). Resistin stimulated proliferation, migration, and capillary-like tube formation in cultured human aortic ECs (HAECs). It also up-regulated VEGF-R1, VEGF-R2, and MMP-1 and MMP-2 expression, as mRNA and protein in HAECs, as well as elicited a transient activation of ERK1/2 and MAPK p38. These cascades seemed to mediate the proangiogenic effect of adiponectin, as their selective inhibitors suppressed adiponectin-induced HAEC proliferation and migration (Mu et al., 2006).
Neuropeptide-Y (NPY) is a 36-amino acid peptide that belongs to a family of highly conserved peptides, including peptide-YY and pancreatic polypeptide. NPY is widely distributed in the nervous system, where it is thought to act as a neurotransmitter, being mainly released from sympathetic nerve fibers. NPY, along other members of its family, binds GPRs, referred to as Y-Rs. Six subtypes of Y-Rs have been identified (from Y1-R to Y6-R), and NPY preferentially binds Y1-R, Y2-R, and Y5-R subtypes. The physiological functions of NPY include the regulation of blood pressure, appetite, and feeding, the modulation of learning and memory, and the control of brain-endocrine axes (Balasubramaniam, 1997; Michel et al., 1998; Cerdá-Reverter and Larhammar, 2000; Spinazzi et al., 2005).
NPY has been reported to stimulate proliferation of rat aorta VSMCs, acting via Y1-Rs and Y2-Rs (Shigeri and Fujimoto, 1993; Zukowska-Grojec et al., 1993). The effect of NPY was bimodal, showing two peaks of proliferation at 10-12 and 10-8/10-7 M concentrations. The first peak was mimicked by Y2-R agonists and suppressed by Y2-R antagonists, and the second peak was mimicked by Y1-R agonists and partially blocked by Y1-R antagonists (Zukowska-Grojec et al., 1998a). NPY has also been shown to stimulate ERK1/2 activity in rat coronary ECs in primary culture (Zukowska-Grojec et al., 1998a). Further studies revealed that NPY at low concentrations (10-12/10-11 M) promoted in vitro angiogenesis by enhancing adhesion, migration, proliferation, and capillary-like tube formation by HUVECs. It also stimulated in vivo angiogenesis in a murine Matrigel plug assay, its potency being similar to that of FGF-2. HUVECs expressed both Y1-R and Y2-R mRNAs, but the in vitro proangiogenic action of NPY seemed to be mainly mediated by the Y2-R subtype, because it was mimicked and suppressed by Y2-R agonists and antagonists, respectively (Zukowska-Grojec et al., 1998b). The main involvement of Y2-Rs has been confirmed by the demonstration that the in vivo and in vitro angiogenic effect of NPY was impaired in Y2-R KO mice (Lee et al., 2003). Moreover, a selective Y2-R agonist enhanced collateral-dependent blood flow in a rat model of peripheral artery disease (bilateral occlusion of the femoral artery distal to the inguinal ligament) (Cruze et al., 2007). More recent findings showed that NPY promoted in vitro angiogenic activity of HUVECs through not only Y1-Rs and Y2-Rs but also Y5-Rs. The effect required the participation of all three R subtypes, the Y5-R probably acting as an enhancer (Movafagh et al., 2006). It has also been shown that NPY-induced vessel growth decreased markedly with age in mice (from 2 to 18 months of age), the impairment being associated with the down-regulation of Y2-R mRNA (Kitlinska et al., 2002).
HUVECs expressed not only Y1-Rs, Y2-Rs, and Y5-Rs but also NPY, as mRNA and protein, and the NPY-converting enzyme dipeptidylpeptidase IV (DPPIV). DP-PIV terminated the Y1-R binding activity of NPY by cleaving the Tyr1–Pro2 bond and transforming it to NPY(3–36), an agonist of Y2-Rs (Zukowska-Grojec et al., 1998b). DPPIV expression decreased in mouse ECs with aging (Kitlinska et al., 2002). On the basis of these results, these investigators proposed that "endothelium is not only the site of action of NPY, but also the site of an autocrine NPY system, which, together with sympathetic nerve" terminals, may play a pivotal role in angiogenesis regulation.
The proliferogenic effect of NPY on ECs and VSMCs might be implicated in the development and progression of postangioplasty restenosis and atherosclerosis (Kuo and Zukowska, 2007). A common polymorphism of the prepro-NPY gene with Leu7 to Pro7 substitution has been reported to highly correlate with elevated total and low-density lipoprotein cholesterol levels and increased carotic artery intima-media thickening (Niskanen et al., 2000; Karvonen et al., 2001). This contention has been experimentally supported by findings showing that NPY accelerated postangioplasty occlusion of rat carotid artery (Li et al., 2003b). Y1-R, Y2-R, and to a lesser extent Y5-R mRNAs were up-regulated within 24 h in operated artery compared with the contralateral vessel and DP-PIV mRNA was down-regulated, thereby enhancing the Y1-R-mediated VSMC proliferative effect of NPY. The increased expression of Y1-Rs and Y5-Rs but not Y2-Rs persisted until 14 days after the operation. The local application of the NPY dose dependently increased neointima formation and media thickening. The treatment with Y1-R and Y5-R antagonists prevented carotic occlusion, suggesting a new possible therapeutic strategy for avoiding postangioplastic restenosis.
Of great interest, NPY, via both Y2-Rs and Y5-Rs, has been reported to play a major role in promoting the growth and neovascularization of neuroblastomas (Kitlinska, 2007). Aggressive neuroblastomas highly expressed NPY and its Rs, and high plasma levels of NPY were frequently correlated with a poor clinical outcome.
H. Vasoactive Intestinal Peptide and Pituitary Adenylate Cyclase-Activating Polypeptide
Vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase-activating polypeptide (PACAP) are members of a family of structurally related peptides that includes secretin, glucagon, glucagon-like peptides, growth hormone-releasing hormone, gastric inhibitory peptide, parathyroid hormone, and exendins. VIP is a highly basic 28-amino acid C-amidated peptide, whereas PACAP is a basic 38-amino acid C-amidated peptide. They display a high degree of homology in their N-terminal sequence, and act via GPRs, named PACAP/VIP Rs. Three subtypes of PACAP/VIP Rs have been identified, whose names and binding potency are as follows: 1) PAC1-R, PACAP
PACAP; and 3) VPAC2-R, VIP = PACAP. VIP and PACAP and their Rs are widely distributed in the body and exert multiple actions, including the modulation of immune and inflammatory responses (Harmar et al., 1998; Vaudry et al., 2000; Conconi et al., 2006).
VIP and PACAP(1–27) were found to increase VEGF expression in lung cancer cells, through a mechanism involving the activation of the PKA- but not the ERK1/2-dependent cascade (Casibang et al., 2001; Moody et al., 2002). Similarly, VIP and PACAP(1–27) have been shown to raise VEGF mRNA expression within 60 min in the androgen-responsive prostate carcinoma-derived cell line LNCaP, and the effect was due to an increase at the transcriptional level, because VEGF mRNA stability was decreased. The effect was mediated by the VPAC1-R, because the agonists of this R but not of VPAC2-R, mimicked VIP and PACAP(1–27) action. Moreover, it occurred via the activation of PKA-, PI3K-, and ERK1/2-dependent pathways, because it was suppressed by H89, wortmanin, and PD98059 exposure (Collado et al., 2004, 2005). Hypoxia up-regulated VIP expression in LNCaP cells, and VIP raised the expression of PAC1-Rs and VPAC1-Rs and decreased that of VPAC2-Rs. VIP did not affect the expression of HIF-1, but increased its translocation from the cytosolic compartment to the nucleus (Collado et al., 2006).
Using a rat sponge model, Hu et al. (1996) showed that daily (for up 14 days) injections of high doses of VIP (1 nmol) evoked intense neovascularization, as assessed by 133Xe clearance technique (for blood flow estimation) and morphometry. Lower doses of VIP (10 pmol) were ineffective but when administered with a subthreshold dose of interleukin-1 evoked an angiogenic response similar to that observed with the higher doses of VIP.
Substance P is a C-amidated decapeptide that belongs, along with neurokinin-A, neurokinin-B, and neuropeptide-K, to the tachykinin family. Tachykinins act via three GPR subtypes, referred to as NK1-R, NK2-R, and NK3-R. Substance P preferentially binds the NK1-R, which activates the phospholipase C (PLC)/PKC-dependent cascade (Nussdorfer and Malendowicz, 1998; Harrison and Geppetti, 2001). Substance P is released from the peripheral terminals of sensory nerve fibers, and evidence has been provided that it may mediate acute inflammatory responses by inducing, via NK1-Rs, vascular permeability, plasma extravasation, and edema (Richardson and Vasko, 2002).
Substance P and a selective NK1-R agonist were found to enhance capillary growth in vivo in a rabbit cornea assay, and to stimulate proliferation and migration in vitro of different EC types, including HUVECs. NK2-R and NK3-R agonists were ineffective, whereas substance P antagonists blocked the response (Ziche et al., 1990). Fan et al. (1993) confirmed the in vivo proangiogenic action of substance P in a rat sponge assay and showed that the effect was suppressed by a selective NK1-R antagonist. The angiogenic effects of substance P were prevented by NG-nitro-L-arginine, suggesting the involvement of NOS/NO-dependent signaling (Ziche et al., 1994).
In vivo experiments showed that endogenous substance P could be implicated in the neoangiogenesis connected with neurogenic inflammation (Seegers et al., 2003). Substance P and capsaicin, which induces substance P release from sensory nerve terminals, were injected in the rat knee and animals were sacrificed 24 h later. Both chemicals increased vascular density in synovia and EC proliferation. The coinjection of a selective NK1-R antagonist attenuated the effect of substance P and capsaicin, whereas that of a NK2-R antagonist was ineffective.
The main features of nonclassic proangiogenic factors are summarized in Table 2. The bulk of evidence indicates that a major role is played by EPO, Ang-II, ET-1, AM, and NPY, which all display intense in vitro and in vivo proangiogenic activity and promote tumor growth and vascularization. The proangiogenic activity of PAMP, urotensin-II, adipokines, VIP/PACAP, and substance P seems to be of minor relevance, but this may depend on the fact that it has been far less investigated. ANG-II, ET-1, AM, PAMP, resistin, and VIP up-regulate the VEGF/VEGF-R system, whereas leptin and adiponectin exhibit positive interactions with angiopoietin-2 and FGF-2, respectively. The possible interactions of EPO with the classic angiogenic factors have not been studied, but findings suggest that it enhances ET-1 expression in and release from ECs. Selective R antagonists are available for many nonclassic proangiogenic factors (e.g., ANG-II, ET, AM, PAMP, urotensin-II, NPY, and VIP), which could make them possible targets of antineoplastic therapeutic strategies.
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IV. Nonclassic Endogenous Inhibitors of Angiogenesis |
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Somatostatin is a regulatory peptide, which had been initially described as a hypothalamic inhibiting releasing hormone of the pituitary growth hormone. Two biologically active forms of somatostatin, which derive from the C-terminal portion of prosomatostatin, are recognized: somatostatins 14 and 28. Somatostatin acts via five subtypes of GPRs, referred to as sst1-R, sst2-R, sst3-R, sst4-R, and sst5-R. Somatostatin and its Rs are widely distributed in tissues and organs, where they exert multiple actions, including inhibition of cell growth and angiogenesis, especially in neoplastic tissues (Patel, 1999; Csaba and Dournaud, 2001; Garcia de la Torre et al., 2002; Olias et al., 2004).
Investigations carried out with PCR and immunocytochemistry techniques showed that human blood vessels expressed high levels of sst1-Rs and low levels of sst2-Rs and sst4-Rs (Curtis et al., 2000). They also showed that HUVECs expressed sst1-R and sst4-R mRNAs and also sst2-R mRNA after repeated passages. In partial contrast with these findings, other studies reported that sst2-Rs were expressed in the proliferating angiogenic sprouts of human vascular endothelium, but not in quiescent ECs. They were present at high density in proliferating blood vessels of tumors (Watson et al., 2001) and could represent an elective target in antineoplastic therapy (Gulec et al., 2001). There is proof that the sst2-R-mediated antiangiogenic action of somatostatin could either be direct, involving the inhibition of EC proliferation (Danesi et al., 1997), or indirect, being mediated by the suppression of production of growth factors, including VEGF (Cascinu et al., 2001; Mentlein et al., 2001).
Further findings indicated the prevalent involvement of sst3-Rs in the antitumoral effect of somatostatin (Florio et al., 2003). Somatostatin exerted an antiproliferative action on bovine aortic ECs (BAECs) and the EC line EAhy926 (originated by fusion of HUVECs with A549 cell line), and the effect was abolished by a selective sst3-R antagonist. However, the inhibition of proliferation probably occurred via a synergism with other R subtypes, because BAECs, expressing sst1-Rs, sst3-Rs, and sst5-Rs, were more sensitive than EAhy926 cells, expressing only sst3-Rs. Human embryo kidney-derived cells were implanted into nude mice, and the angiogenesis and growth of the tumor was impaired by the peritumor injection of somatostatin, which acted via sst3-Rs negatively coupled to ERK1/2 and NOS.
Ghrelin is a 28-amino acid peptide, that acts as an endogenous ligand of the growth hormone secretagogue R (GHS-R). Two subtypes of GHS-Rs have been identified: the fully functional GHS-R1a and the biologically inactive GHS-R1b. Ghrelin and its Rs are widely expressed in tissues and organs. Although the main biological effects of ghrelin are thought to be the stimulation of pituitary growth hormone release and food intake, the peptide has be found to exert many other actions, including a protective effect on cardiovascular system (Kojima et al., 2001; van der Lely et al., 2004; Davenport et al., 2005; Kojima and Kangawa, 2005; Camiña, 2006; Cao et al., 2006).
Ghrelin and GHS-Rs have been shown to be expressed in HUVECs (Conconi et al., 2004). Earlier investigations reported that ghrelin inhibited doxorubicin-induced apoptosis of porcine aortic ECs, via the ERK1/2 and PI3K/Akt signaling cascades (Baldanzi et al., 2002). However, further studies did not confirm this observation: ghrelin did not affect the basal apoptotic rate of HUVECs cultured in normal growth medium (Belloni et al., 2004) or raise it in cultured rat brain microvascular ECs and HUVECs. Moreover, ghrelin suppressed the antiapoptotic effect of FGF-2 (Baiguera et al., 2004; Conconi et al., 2004). Ghrelin was found to lower the proliferative activity of rat ECs and HUVECs and to exert a marked inhibitory action on capillary-like tube formation by these types of ECs cultured on Matrigel. It also counteracted the angiogenic effect of FGF-2 in the CAM assay (Baiguera et al., 2004; Conconi et al., 2004). The proliferogenic effect of ghrelin on ECs was annulled by the GHS-R antagonist D-Lys3-growth hormone releasing peptide-6, and the peptide did not increase lactate dehydrogenase release from cultured ECs, indicating that the antiangiogenic action of ghrelin was mediated by the GHS-R and did not ensue from an aspecific toxic action. Baiguera et al. (2004) demonstrated that FGF-2 enhanced tyrosine kinase and ERK1/2 activities in rat brain ECs. Ghrelin significantly decreased tyrosine kinase and ERK1/2 activities, and effectively counteracted the effect of FGF-2, thereby strongly suggesting that the mechanism underlying its antiangiogenic action involved the inhibition of these cascades.
Natriuretic peptides are a family of small proteins that modulate salt and water balance and vascular biology. This family includes atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP) and C-type natriuretic peptide (CNP), which in humans are 28-, 32-, and 53-amino acid residue peptides, respectively. ANP and BNP are predominantly synthesized in the heart, whereas CNP is produced by ECs (Levin et al., 1998). Natriuretic peptides act via at least three subtypes of receptors: the A-R and B-R subtypes are positively coupled to guanylate cyclase, thereby stimulating cGMP production and subsequently activating PKG and modulating potassium channels; the C-R subtype, also named clearance receptor, is not coupled to or inhibits guanylate cyclase. Their binding potency is as follows: A-R subtype, ANP = BNP >> CNP; B-R subtype, CNP selective; and C-R subtype, ANP = BNP = CNP (Silberbach and Roberts, 2001).
Evidence has been provided that natriuretic peptides inhibited human EC proliferation (Itoh et al., 1992). Further studies showed that ANP and CNP impaired basal and ET- or hypoxia-stimulated VEGF production in human ECs and VSMCs cultured in vitro, as well as their growth (Pedram et al., 1997a,b). These investigators subsequently reported that natriuretic peptides, acting via either A-Rs and B-Rs or C-Rs, blocked VEGF signaling in primary cultures of BAECs (i.e., ERK1/2-dependent c-Jun N-terminal kinase and to a lesser degree MAPK p38), thereby suppressing VEGF-induced EC proliferation, migration, and capillary-like tube formation on Matrigel (Pedram et al., 2001). Hence, natriuretic peptides can be considered one of the first described endogenous inhibitors of VEGF-modulated angiogenesis.
Investigations have also demonstrated that ANP mRNA was up-regulated in rat ventricular myocardium in the early phases of ischemia, this being preceded by an increase in HIF-1 expression. Accordingly, hypoxia or HIF-1 activation was found to induce ANP gene expression in rat neonatal cardiomyocytes and the rat ventricular myoblast cell line H9c2 (Chun et al., 2003). The up-regulation of ANP and BNP expression in ischemic myocardium have been confirmed in humans, but this was not associated with enhanced VEGF gene expression (Rück et al., 2004). Nevertheless, the overexpression of anti-angiogenic natriuretic peptides could be one of the causes of the relative inefficiency of spontaneous neoangiogenesis in some patients with chronic heart ischemia (angina pectoris), as well as of their poor response to clinical trials with proangiogenic agents.
The main features of nonclassic antiangiogenic factors are shown in Table 2. Available findings identify somatostatin as a major suppressive factor of tumor growth and vascularization, but experimental studies on its in vitro and in vivo antiangiogenic action are surprisingly almost completely lacking. The antiangiogenic activity of ghrelin has been well demonstrated both in vitro and in vivo assays, but investigations on its possible antineoplastic action have not yet been carried out. The same is true for natriuretic peptides, whose antiangiogenic action has been studied only in vitro. Of interest, somatostatin and perhaps natriuretic peptides have been reported to down-regulate the VEGF system, thereby suggesting an indirect mechanism of action.
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V. Conclusions and Perspectives |
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It is well established that the angiogenic phenotype results from the imbalance between positive and negative regulator factors, so that the contribution of each classic and/or nonclassic angiogenic factor may play a different role in the definition of the angiogenic phenotype. Increased production of angiogenic stimuli and/or reduced production of classic and/or nonclassic angiogenic inhibitors may lead to abnormal neovascularization, such as that occurring in cancer, chronic inflammatory diseases, diabetic retinopathy, macular degeneration, and cardiovascular disorders.
The development of a clinical trial requires the identification and characterization of the physiological targets involved in angio-stimulatory and angio-inhibitory activities. Much research effort has been concentrated on the role of angiogenesis in cancer, and inhibition of angiogenesis is a major area of therapeutic development for the treatment of this disease. New pathophysiological concepts generated in the past few decades have given rise to the development of a large variety of new drugs to interfere with angiogenesis. The target of antiangiogenic therapy is the vascular EC rather than the tumor cell. In fact, whereas conventional chemotherapy, radiotherapy, and immunotherapy are directed against tumor cells, antiangiogenic therapy is aimed at the tumor vasculature and will either cause tumor regression or keep the tumor in a state of dormancy. The predominant mode of action of antiangiogenic agents clinically tested to date in cancer trials has been cytostatic. Many of the cytostatic agents under clinical investigation have been shown to have reversibility of their activity upon removal of the agent. This implies that the benefit of administration may be limited to the time during which a physiologically concentration of the agent is available. Preclinical and clinical studies have made it increasingly clear that strategies that target tumor blood vessel networks ultimately will be most effective if used in conjunction with, or adjuvant to, conventional anticancer therapies.
Detailed knowledge of the mechanism of action and expression as well as the interactions of the new nonclassic endogenous regulators of angiogenesis with their Rs will provide new insights that are essential for the future development of chemical compounds that can modulate the activity of these new nonclassic endogenous regulators and may have potential for antitumor activity. In fact, tumors and other angiogenic pathologies exploit redundant mechanisms to induce angiogenesis, and neutralization of multiple factors, including both classic and nonclassic regulators, may be required to suppress tumor growth. In this context, a paradigmatic example is represented by the characterization of ET-1 and AM and their Rs as new vascular markers in tumors, providing a better understanding of novel targeting approaches for cancer treatment. The recognition by clinicians of the angiogenesis-modulatory properties of common drugs is important in the development and future application of angiogenesis-inhibitory therapies. The linkage between the laboratory and the clinic, which brought this important new development to the patient, must be maintained to further our understanding of the role of angiogenesis in normal physiology and disease, to develop and validate intermediate and surrogate markers of benefit, and to advance to the optimal use of antiangiogenic molecules.
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Acknowledgements |
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Footnotes |
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This work was supported by grants from the Italian Association for Cancer Research, Italian Ministry of University and Research (MIUR) (FIRB 2001, PRIN 2005, and CARSO Project 72/2), and the Italian Foundation for Neuroblastoma Research (to D.R.) and from MIUR (FIRB 2001 and PRIN 2005) and the Veneto Region Department of Health (RSF 2005) (to G.G.N.).
This article is available online at http://pharmrev.aspetjournals.org.
1 Abbreviations: VEGF, vascular endothelial growth factor; FGF-2, fibroblast growth factor-2; TGF, transforming growth factor; PDGF, platelet-derived growth factor; EC, endothelial cell; MMP, matrix metalloproteinase; VSMC, vascular smooth muscle cell; R, receptor; ECM, extracellular matrix; ET, endothelin; AM, adrenomedullin; EPO, erythropoietin; HIF, hypoxia-inducible transcription factor; JAK, Janus kinase; STAT, signal transducer and activator of transcription; PI3K, phosphatidylinositol 3-kinase; CAM, chorioallantoic membrane; ANG, angiotensin; ACE, angiotensin-converting enzyme; GPR, G protein-coupled receptor; AT1-R, angiotensin II-type 1 receptor; AT2-R, angiotensin II-type 2 receptor; KO, knockout; NO, nitric oxide; NOS, nitric-oxide synthase; PD123319, S-(+)-1-([4-(dimethylamino)-3-methylphenyl]methyl)-5-(diphenylacetyl)-4,5,6,7-tetrahydro-1H-imidazo(4,5-c)pyridine-6-carboxylic acid; ETA-R, endothelin type A receptor; ETB-R, endothelin type B receptor; HUVEC, human umbilical vein endothelial cell; BQ788, N-cis-2,6-dimethylpiperidinocarbonyl-L-
-methylleucyl-D-1-methoxycarbonyl-tryptophanyl-D-norleucine; BQ123, cyclo(D-Asp-Pro-D-Val-Leu-D-Trp); ABT-627, [2R-(4-methoxyphenyl)-4S-(1,3-benzodioxol-5-yl)-1-(N,N-di(n-butyl)aminocarbonyl-methyl)-pyrroli-dine-3R-carboxylic acid]; PGE2, prostaglandin E2; PAMP, proadrenomedullin N-terminal 20 peptide; CRLR, calcitonin receptor-like receptor; CGRP, calcitonin gene-related peptide; RAMP, receptor-activity-modifying protein; AM1-R, adrenomedullin type 1 receptor; AM2-R, adrenomedullin type 2 receptor; MAPK, mitogen-activated protein kinase; PCR, polymerase chain reaction; UT-R, urotensin II receptor; ACT058362, palosuran, 1-[2-(4-benzyl-4-hydroxy-piperidin-1-yl)-ethyl]-3-(2-methyl-quinolin-4-yl)-urea sulfate salt; Ob-R, leptin receptor; ERK, extracellular signal-regulated kinase; adipoR, adiponectin receptor; PK, protein kinase; HAEC, human aortic endothelial cell; NPY, neuropeptide-Y; Y1-R to Y6-R, neuropeptide-Y type to 6 receptor; DPPIV, dipeptidylpeptidase IV; VIP, vasoactive intestinal peptide; PACAP, pituitary adenylate cyclase-activating polypeptide; PAC1-R, pituitary adenylate cyclase-activating polypeptide type 1 receptor; VPAC1-R, vasoactive intestinal peptide/pituitary adenylate cyclase-activating polypeptide type 1 receptor; VPAC2-R, vasoactive intestinal peptide/pituitary adenylate cyclase-activating polypeptide type 2 receptor; PD98059, 2'-amino-3'-methoxyflavone; NK1-R to NK3-R, neurokinin type 1 to 3 receptor; PLC, phospholipase C; sst1-R to sst5-R, somatostatin type 1 to 5 receptor; BAEC, bovine aortic endothelial cell; GHS-R, growth hormone secretagogue receptor; ANP, atrial natriuretic peptide; BNP, brain natriuretic peptide; CNP, C-type natriuretic peptide. 
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References |
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Top |
|---|
Abasolo I, Montuenga LM, and Calvo A (2006) Adrenomedullin prevents apoptosis in prostate cancer cells. Regul Pept 133: 115-122.[CrossRef][Medline]
Abe M, Sata M, Nishimatsu H, Nagata D, Suzuki E, Terauchi Y, Kadowaki T, Minamino N, Kangawa K, Matsuo H, et al. (2003) Adrenomedullin augments collateral development in response to acute ischemia. Biochem Biophys Res Commun 306: 10-15.[CrossRef][Medline]
Abe M, Sata M, Suzuki E, Takeda R, Takahashi M, Nishimatsu H, Nagata D, Kangawa K, Matsuo H, Nagai R, et al. (2006) Effects of adrenomedullin on acute ischaemia-induced collateral development and mobilization of bone-marrow derived cells. Clin Sci 111: 381-387.[CrossRef][Medline]
Adachi Y, Takeuchi T, Sonobe H, and Ohtsuki Y (2006) An adiponectin receptor, T-cadherin, was selectively expressed in intratumoral capillary endothelial cells in hepatocellular carcinoma: possible cross talk between T-cadherin and FGF-2 pathways. Virchows Arch 448: 311-318.[CrossRef][Medline]
Ahima RS and Flier JS (2000) Leptin. Annu Rev Physiol 62: 413-437.[CrossRef][Medline]
Ahmed SI, Thompson J, Coulson JM, and Woll PJ (2000) Studies on the expression of endothelin, its receptor subtypes and converting enzymes in lung cancer and in human bronchial epithelium. Am J Respir Cell Mol Biol 22: 422-431.
Albertin G, Rucinski M, Carraro G, Forneris M, Andreis PG, Malendowicz LK, and Nussdorfer GG (2005) Adrenomedullin and vascular endothelium growth factor genes are overexpressed in the regenerating rat adrenal cortex, and AM and VEGF reciprocally enhance their mRNA expression in cultured rat adrenocortical cells. Int J Mol Med 16: 431-435.[Medline]
Albertin G, Ruggero M, Guidolin D, and Nussdorfer GG (2006) Gene silencing of human RAMP2 mediated by short-interfering RNA. Int J Mol Med 18: 531-535.[Medline]
Ames RS, Sarau HM, Chambers JK, Willette RN, Aiyar NV, Romanic AM, Louden CS, Foley JJ, Sauermelch CF, Coatney RW, et al. (1999) Human urotensin-II is a potent vasoconstrictor and agonist for the orphan GPR14. Nature 401: 282-286.[CrossRef][Medline]
Anagnostou A, Lee ES, Kessimian N, Levinson R, and Steiner M (1990) Erythropoietin has a mitogenic and positive chemotactic effect on endothelial cells. Proc Natl Acad Sci U S A 87: 5978-5982.
Anagnostou A, Liu Z, Steiner M, Chin K, Lee ES, Kessimian N, and Noguchi CT (1994) Erythropoietin receptor mRNA expression in human endothelial cells. Proc Natl Acad Sci U S A 91: 3974-3978.
Arita Y, Kihara S, Ouchi N, Maeda K, Kuriyama H, Okamoto Y, Kumata M, Hotta K, Nishida M, Takahashi M, et al. (2002) Adipocyte-derived plasma protein adiponectin acts as a platelet-derived growth factor-BB-binding protein and regulates growth factor-induced common postreceptor signal in vascular smooth muscle cell. Circulation 105: 2893-2898.
Asham E, Shankar A, Loizidou M, Fredericks S, Miller K, Boulos PB, Burnstock G, and Taylor I (2001) Increased endothelin-1 in colorectal cancer and reduction of tumor growth by ET(A) receptor antagonism. Br J Cancer 85: 1759-1763.[CrossRef][Medline]
Ashley RA, Dubuque SH, Dvorak B, Woodward SS, William SK, and Kling PT (2002) Erythropoietin stimulates vasculogenesis in neonatal rat mesenteric microvascular endothelial cells. Pediatr Res 51: 472-478.[CrossRef][Medline]
Bagnato A, Rosanó L, Di Castro V, Albini A, Salani D, Varmi M, Nicotra MR, and Natali PG (2001) Endothelin receptor blockade inhibits proliferation of Kaposi's sarcoma cells. Am J Pathol 158: 841-847.
Bagnato A and Spinella F (2003) Emerging role of endothelin-1 in tumor angiogenesis. Trends Endocrinol Metab 14: 44-50.[CrossRef][Medline]
Baiguera S, Conconi MT, Guidolin D, Mazzocchi G, Malendowicz LK, Parnigotto PP, Spinazzi R, and Nussdorfer GG (2004) Ghrelin inhibits in vitro angiogenic activity of rat brain microvascular endothelial cells. Int J Mol Med 14: 849-854.[Medline]
Balasubramaniam A (1997) Neuropeptide Y family of hormones: receptor subtypes and antagonists. Peptides 18: 445-457.[CrossRef][Medline]
Baldanzi G, Filigheddu N, Cutrupi B, Catapano F, Bonissoni S, Fubini A, Malan D, Baj G, Granata R, Broglio F, et al. (2002) Ghrelin and desacyl ghrelin inhibit cell death in cardiomyocytes and endothelial cells through ERK1/2 and PI3-kinase/AKT. J Cell Biol 159: 1029-1037.
Balkwill F and Mantovani A (2001) Inflammation and cancer: back to Virchow? Lancet 357: 539-545.[CrossRef][Medline]
Basilico C and Moscatelli D (1992) The FGF family of growth factors and oncogenes. Adv Cancer Res 59: 115-165.[Medline]
Belloni AS, Albertin G, Forneris M, and Nussdorfer GG (2001) Pro-adrenomedullin derived peptides as autocrine-paracrine regulators of cell growth. Histol Histopathol 16: 1263-1274.[Medline]
Belloni AS, Guidolin D, Salmaso R, Bova S, Rossi GP, and Nussdorfer GG (2005) Adrenomedullin, ANP and BNP are colocalized in a subset of endocrine cells in the rat heart. Int J Mol Med 15: 567-571.[Medline]
Belloni AS, Macchi C, Rebuffat P, Conconi MT, Malendowicz LK, Parnigotto PP, and Nussdorfer GG (2004) Effects of ghrelin on the apoptotic deletion rate of different types of cells cultured in vitro. Int J Mol Med 14: 165-167.[Medline]
Belloni AS, Petrelli L, Guidolin D, De Toni R, Bova S, Spinazzi R, Gerosa G, Rossi GP and Nussdorfer GG (2006) Identification and localization of adrenomedullin-storing cardiac mast cells. Int J Mol Med 17: 709-713.[Medline]
Belloni AS, Rossi GP, Andreis PG, Aragona F, Champion HC, Kadowitz PJ, Murphy WA, Coy DH, and Nussdorfer GG (1999) Proadrenomedullin N-terminal 20 peptide (PAMP), acting through PAMP(12–20)-sensitive receptors, inhibits Ca2+-dependent agonist-stimulated secretion of human adrenal glands. Hypertension 33: 1185-1189.
Betowski J (2003) Adiponectin and resistin: new hormones of white adipose tissue. Med Sci Monit 9: RA55-RA61.[Medline]
Bohlius J, Langensiepen S, Schwarzer G, Seidenfeld J, Piper M, Bennett C, and Engert A (2005) Recombinant human erythropoietin and overall survival in cancer patients: results of a comprehensive metaanalysis. J Natl Cancer Inst 97: 489-498.
Bouloumié A, Drexler HCA, Lafontan M, and Busse R (1998) Leptin, the product of ob gene, promotes angiogenesis. Circ Res 83: 1059-1066.
Bråkenhielm E, Veitonmäki N, Cao R, Kihara S, Matsuzawa Y, Zhivotovsky B, Funahashi T, and Cao Y (2004) Adiponectin-induced antiangiogenesis and antitumor activity involve caspase-mediated endothelial cell apoptosis. Proc Natl Acad Sci U S A 101: 2476-2481.
Brooks PC, Clark RAF, and Cheresh DA (1994) Requirement of vascular integrin v3 for angiogenesis. Science 264: 569-571.
Brooks PC, Stromblad S, Sanders LC, Von Schalscha TL, Aimes RT, Stetler-Stevenson WG, Quigley JP, and Cheresh DA (1996) Localization of matrix metalloproteinase MMP-2 to the surface of invasive cells by interactions with integrin v3. Cell 85: 683-693.[CrossRef][Medline]
Calabro P, Samudio I, Willerson JT, and Yeh ETH (2004) Resistin promotes smooth muscle cell proliferation through activation of extracellular signal-regulated kinase 1/2 and phosphatidylinositol 3-kinase pathways. Circulation 110: 3335-3340.
Calvillo L, Latini R, Kajstura J, Leri A, Anversa P, Ghezzi P, Salio M, Cerami A, and Brines M (2003) Recombinant human erythropoietin protects the myocardium from ischemia-reperfusion injury and promotes beneficial remodeling. Proc Natl Acad Sci U S A 100: 4802-4806.
Camiña JP (2006) Cell biology of the ghrelin receptor. J Neuroendocrinol 18: 65-76.[CrossRef][Medline]
Cao JM, Ong H, and Chen C (2006) Effects of ghrelin and synthetic GH secretagogue on the cardiovascular system. Trends Endocrinol Metab 17: 13-18.[CrossRef][Medline]
Cao R, Bråkenhielm E, Wahlestedt C, Thyberg J, and Cao Y (2001) Leptin induces vascular permeability and synergistically stimulates angiogenesis with FGF-2 and VEGF. Proc Natl Acad Sci U S A 98: 6390-6395.
Carlini RG, Dusso AS, Obialo CI, Alvarez UM, and Rothstein M (1993) Recombinant human erythropoietin (rHuEPO) increases endothelin-1 release by endothelial cells. Kidney Int 43: 1010-1014.[Medline]
Carlini RG, Reyes AA and Rothstein M (1995) Recombinant human erythropoietin stimulates angiogenesis in vitro. Kidney Int 47: 740-745.[Medline]
Caron KM and Smithies O (2001) Extreme hydrops fetalis and cardiovascular abnormalities in mice lacking a functional adrenomedullin gene. Proc Natl Acad Sci U S A 98: 615-619.
Cascinu S, Del Ferro E, Ligi M, Staccioli MP, Giordani P, Catalano V, Agostinelli R, Muretto P, and Catalano G (2001) Inhibition of vascular endothelial growth factor by octreotide in colorectal cancer patients. Cancer Invest 19: 8-12.[CrossRef][Medline]
Casibang M, Purdom S, Jacowlew S, Neckers L, Zia F, Ben-Av P, Hla T, You L, Jablons DM, and Moody TW (2001) Prostaglandin E2 and vasoactive intestinal peptide increase vascular endothelial cell growth factor mRNAs in lung cancer cells. Lung Cancer 31: 203-212.[CrossRef][Medline]
Cerdá-Reverter JM and Larhammar D (2000) Neuropeptide Y family of peptides: structure, anatomical expression, function, and molecular evolution. Biochem Cell Biol 78: 371-392.[CrossRef][Medline]
Chua CC, Hamdy RC, and Chua BH (1998) Upregulation of vascular endothelial growth factor by angiotensin II in rat heart endothelial cells. Biochim Biophys Acta 1401: 187-194.[Medline]
Chun YS, Hyun JY, Kwak YG, Kim IS, Kim CH, Choi E, Kim MS, and Park JW (2003) Hypoxic activation of the atrial natriuretic peptide gene promoter through direct and indirect actions of hypoxia-inducible factor-1. Biochem J 370: 149-157.[CrossRef][Medline]
Clozel M, Binkert C, Birker-Robaczewska M, Boukhadra C, Ding SS, Fischli W, Hess P, Mathys B, Morrison K, Müller C, et al. (2004) Pharmacology of the urotensin II receptor antagonist palosuran (ACT-058362; 1-[2-(4-benzyl-4-hydroxy-piperidin-1-yl)-ethyl]-3-(2-methyl-quinolin-4-yl)-urea sulfate salt): first demonstration of a pathophysiological role of the urotensin system. J Pharmacol Exp Ther 311: 204-212.
Cohen B, Barkan D, Levy Y, Goldberg I, Fridman E, Kopolovic J, and Rubinstein M (2001) Leptin induces angiopoietin-2 expression in adipose tissues. J Biol Chem 276: 7697-7700.
Collado B, Gutierrez-Cañas I, Rodriguez-Henche N, Prieto JC, and Carmena MJ (2004) Vasoactive intestinal peptide increases vascular endothelial growth factor expression and neuroendocrine differentiation in human prostate cancer LNCaP cells. Regul Pept 119: 69-75.[CrossRef][Medline]
Collado B, Sanchez MG, Diaz-Laviada I, Prieto JC, and Carmena MJ (2005) Vasoactive intestinal peptide (VIP) induces c-fos expression in LNCaP prostate cancer cells through a mechanism that involves Ca2+ signalling: implication in angiogenesis and neuroendocrine differentiation. Biochim Biophys Acta 1744: 224-233.[Medline]
Collado B, Sanchez-Chapado M, Prieto JC, and Carmena MJ (2006) Hypoxia regulation of expression and angiogenic effects of vasoactive intestinal peptide (VIP) and VIP receptors in LNCaP prostate cancer cells. Mol Cell Endocrinol 249: 116-122.[Medline]
Conconi MT, Nico B, Guidolin D, Baiguera S, Spinazzi R, Rebuffat P, Malendowicz LK, Vacca A, Carraro G, Parnigotto PP, et al. (2004) Ghrelin inhibits FGF-2-mediated angiogenesis in vitro and in vivo. Peptides 25: 2179-2185.[CrossRef][Medline]
Conconi MT, Spinazzi R, and Nussdorfer GG (2006) Endogenous ligands of PACAP/VIP receptors in the autocrine-paracrine regulation of the adrenal gland. Int Rev Cytol 249: 1-51.[Medline]
Cormier-Regards S, Nguyen SV, and Claycomb WC (1998) Adrenomedullin gene expression is developmentally regulated and induced by hypoxia in rat ventricular cardiac myocytes. J Biol Chem 273: 17787-17792.
Crandall DL, Hausman GJ, and Kral JG (1997) A review of the microcirculation of adipose tissue: anatomic, metabolic, and angiogenic perspectives. Microcirculation 4: 211-232.[Medline]
Cross MJ and Claesson-Welsh L (2001) FGF and VEGF function in angiogenesis: signaling pathways, biological responses and therapeutic inhibition. Trends Pharmacol Sci 22: 201-207.[CrossRef][Medline]
Cruz A, Parnot C, Ribatti D, Corvol P, and Gasc JM (2001) Endothelin-1, a regulator of angiogenesis in the chick chrioallantoic membrane. J Vasc Res 38: 536-545.[CrossRef][Medline]
Cruze CA, Su F, Limberg BJ, Deutch AJ, Stoffolano PJ, Dai HJ, Buchanan DD, Yang HT, Terjung RL, Spruell RD, et al. (2007) The Y2 receptor mediates increases in collateral-dependent blood flow in a model of peripheral arterial insufficiency. Peptides 28: 269-280.[CrossRef][Medline]
Csaba Z and Dournaud P (2001) Cellular biology of somatostatin receptors. Neuropeptides 35: 1-23.[CrossRef][Medline]
Curtis SB, Hewitt J, Yakubovits S, Anzarut A, Hsiang YN, and Buchan AMJ (2000) Somatostatin receptor subtype expression and function in human vascular tissue. Am J Physiol 278: H1815-H1822.
Dameron KM, Volpert OV, Tainsky MA, and Bouck N (1994) Control of angiogenesis in fibroblasts by p53 regulation of thrombospondin-1. Science 265: 1582-1584.
D'Andrea LD, Del Gatto A, Pedone C, and Benedetti E (2006) Peptide-based molecules in angiogenesis. Chem Biol Drug Des 67: 115-126.[CrossRef][Medline]
Danesi R, Agen C, Benelli U, Paolo AD, Nardini D, Bocci G, Basolo F, Campagni A, and Tacca MD (1997) Inhibition of experimental angiogenesis by the somatostatin analogue octreotide acetate (SMS 201–995). Clin Cancer Res 3: 265-272.[Abstract]
Davenport AP (2002) International Union of Pharmacology. XXIX. Update on endothelin receptor nomenclature. Pharmacol Rev 54: 219-226.
Davenport AP and Maguire JJ (2000) Urotensin II: fish neuropeptide catches orphan receptor. Trends Pharmacol Sci 21: 80-92.[CrossRef][Medline]
Davenport AP, Bonner TI, Foord SM, Harmar AJ, Neubig RR, Pin JP, Spedding M, Kojima M, and Kangawa K (2005) International Union of Pharmacology. LVI. Ghrelin receptor nomenclature, distribution and function. Pharmacol Rev 57: 541-546.
Dhanabal M, Ramachandran R, Waterman MJ, Lu H, Knebelmann B, Segal M, and Sukhatme VP (1999) Endostatin induces endothelial cell apoptosis. J Biol Chem 274: 11721-11726.
Dimmeler S and Zeiher AM (2000) Akt takes center stage in angiogenesis signaling. Circ Res 86: 4-5.
Djonov V, Schmid M, Tschanz SA, and Burri PH (2000) Intussusceptive angiogenesis: its role in embryonic vascular network formation. Circ Res 86: 286-292.
D'Orléans-Juste P, Labonté J, Bkaily G, Choufani S, Plante M, and Honorè JC (2002) Function of the endothelin B receptor in cardiovascular physiology and pathophysiology. Pharmacol Ther 95: 221-238.[CrossRef][Medline]
Douglas SA and Ohlstein EH (2000) Human urotensin-II, the most potent mammalian vasoconstrictor identified to date, as therapeutic target for the management of cardiovascular disease. Trends Cardiovasc Med 10: 229-237.[CrossRef][Medline]
Egidy G, Eberl LP, Valdenaire O, Irmler M, Majdi R, Diserens AC, Fontana A, Janzer RC, Pinet F, and Juillerat-Jeanneret L (2000a) The endothelin system in human glioblastoma. Lab Invest 80: 1681-1689.[Medline]
Egidy G, Juillerat-Jeanneret L, Jeannin JF, Korth P, Bosman FT, and Pinet F (2000b) Modulation of human colon tumor-stromal interactions by the endothelin system. Am J Pathol 157: 1863-1874.
Fabre JE, Rivard A, Magner M, Silver M, and Isner JM (1999) Tissue inhibition of angiotensin-converting enzyme activity stimulates angiogenesis in vivo. Circulation 99: 3043-3049.
Fagan KA, McMurthry IF, and Rodman DM (2001) Role of endothelin-1 in lung disease. Respir Res 2: 90-101.[CrossRef][Medline]
Fan TP, Hu DE, Guard S, Gresham GA, and Watling KJ (1993) Stimulation of angiogenesis by substance P and interleukin-1 in the rat and its inhibition by NK1 or interleukin-1 receptor antagonists. Br J Pharmacol 110: 43-49.[Medline]
Farrell F and Lee A (2004) The erythropoietin receptor and its expression in tumor cells and other tissues. The Oncologist 9 (Suppl 5): 18-30.
Feoktistov I, Ryzhov S, Goldstein AE, and Biagioni I (2003) Mast cell-mediated stimulation of angiogenesis: cooperative interaction between A2B and A3 adenosine receptors. Circ Res 92: 485-492.
Fernandez LA, Twickler J, and Mead A (1985) Neovascularization produced by angiotensin II. J Lab Clin Med 105: 141-145.[Medline]
Fernandez-Sauze S, Delfino C, Mabrouk K, Dussert C, Chinot O, Martin PM, Grisoli F, Ouafik L, and Boudouresque F (2004) Effects of adrenomedullin on endothelial cells in the multistep process of angiogenesis: involvement of CRLR/RAMP2 and CRLR/RAMP3 receptors. Int J Cancer 108: 797-804.[CrossRef][Medline]
Ferrara N (2004) Vascular endothelial growth factor: basic science and clinical progress. Endocr Rev 25: 581-611.
Ferrara N, Gerber HP, and Le Couter J (2003) The biology of VEGF and its receptors. Nat Med 9: 669-676.[CrossRef][Medline]
Florio T, Morini M, Villa V, Arena S, Corsaro A, Thellung S, Culler MD, Pfeffer U, Noonan DM, Schettini G, et al. (2003) Somatostatin inhibits tumor angiogenesis and growth via somatostatin receptor-3-mediated regulation of endothelial nitric oxide synthase and mitogen-activated protein kinase activities. Endocrinology 144: 1574-1584.
Flynn MA, Haleen SJ, Welch KM, Cheng XM, and Reynolds EE (1998) Endothelin B receptors on human endothelial and smooth muscle cells show equivalent binding pharmacology. J Cardiovasc Pharmacol 32: 106-116.[CrossRef][Medline]
Folkman J (1995) Angiogenesis in cancer, vascular rheumatoid and other diseases. Nat Med 1: 27-32.[CrossRef][Medline]
Folkman J (2006) Angiogenesis. Annu Rev Med 57: 1-18.[CrossRef][Medline]
Forneris M, Gottardo L, Albertin G, Malendowicz LK, and Nussdorfer GG (2001) Expression and function of adrenomedullin and its receptors in Conn's adenoma cells. Int J Mol Med 8: 675-679.[Medline]
Frede S, Freitag P, Otto T, Heilmaier C, and Fandrey J (2005) The proinflammatory cytokine interleukin 1 and hypoxia cooperatively induce the expression of adrenomedullin in ovarian carcinoma cells through hypoxia inducible factor 1 activation. Cancer Res 65: 4690-4697.
Fujitani Y, Oda K, Takimoto M, Inui T, Okada T, and Urade Y (1992) Autocrine receptors for endothelins in the primary culture of endothelial cells of human umbilical vein. FEBS Lett 298: 79-83.[CrossRef][Medline]
Garayoa M, Martínez A, Lee S, Pio R, An WG, Neckers L, Trepel J, Montuenga LM, Ryan H, Johnson R, et al. (2000) Hypoxia-inducible factor-1 (HIF-1) up-regulates adrenomedullin expression in human cell lines during oxygen deprivation: a possible promotion mechanism of carcinogenesis. Mol Endocrinol 14: 848-862.
García MA, Martin-Santamaria S, De Pascual-Teresa B, Ramos A, Julian M, and Martínez A (2006) Adrenomedullin: a new and promising target for drug discovery. Expert Opin Ther Targets 10: 303-317.[CrossRef][Medline]
Garcia de la Torre N, Wass JAH, and Turner HE (2002) Antiangiogenic effects of somatostatin analogues. Clin Endocrinol (Oxf) 57: 425-441.[CrossRef][Medline]
Ghezzi P and Brines M (2004) Erythropoietin as an antiapoptotic, tissue-protective cytokine. Cell Death Differ 11: 537-544.
Goligorsky MS, Budzikowski AS, Tsukahara H, and Noiri E (1999) Co-operation between endothelin and nitric oxide in promoting endothelial cell migration and angiogenesis. Clin Exp Pharmacol Physiol 26: 269-271.[CrossRef][Medline]
Gonzalez RR, Cherfils S, Escobar M, Yoo JH, Carino C, Styer AK, Sullivan BT, Sakamoto H, Olawaiye A, Serikawa T, et al. (2006) Leptin signaling promotes the growth of mammary tumors and increases the expression of vascular endothelial growth factor (VEGF) and its receptor type two (VEGF-R2). J Biol Chem 281: 26320-26328.
González-Santiago L, Lopez-Ongil S, Griera M, Rodriguez-Puyol M, and Rodriguez-Puyol D (2002) Regulation of endothelin synthesis by extracellular matrix in human endothelial cells. Kidney Int 62: 537-543.[CrossRef][Medline]
Good DJ, Polverini PJ, Rastinejad F, Lebeau MM, Lemons RS, Frazier WA, and Bouck NP (1990) A tumor-suppressor dependent inhibitor of angiogenesis is immunologically and functionally indistinguishable from a fragment of thrombospondin. Proc Natl Acad Sci U S A 87: 6624-6628.
Green H and Kehinde O (1979) Formation of normally differentiated subcutaneous fat pads by an established preadipose cell line. J Cell Physiol 101: 169-171.[CrossRef][Medline]
Gulec SA, Drouant GJ, Fuselier J, Anthony CT, De Heneghan JI, Carpio JB, Coy DH, Murphy WA, and Woltering EA (2001) Antitumor and antiangiogenic effects of somatostatin receptor-targeted in situ radiation with (111)In-DTPA-JIC 2DL. J Surg Res 97: 131-137.[CrossRef][Medline]
Hague S, Zhang L, Oehler MK, Manek S, MacKenzie IZ, Bicknell R, and Rees MC (2000) Expression of the hypoxically regulated angiogenic factor adrenomedullin correlates with uterine leiomyoma (benign smooth muscle tumors) vascular density. Clin Cancer Res 6: 2808-2814.
Haller H, Christel C, Donnenberg L, Thiele P, Lindschau C, and Luft FC (1996) Signal transduction of erythropoietin in endothelial cells. Kidney Int 50: 481-488.[Medline]
Hardee ME, Arcasoy MO, Blackwell KL, Kirkpatrick JP, and Dewhirst MW (2006) Erythropoietin biology in cancer. Clin Cancer Res 12: 332-339.
Harmar AJ, Arimura A, Gozes I, Journot L, Laburthe M, Pisegna JR, Rawlings SR, Robberecht P, Said SI, Szeedharan SP, et al. (1998) International Union of Pharmacology. XVIII. Nomenclature of receptors for vasoactive intestinal peptide and pituitary adenylate cyclase-activating polypeptide. Pharmacol Rev 50: 265-270.
Harrison S and Geppetti P (2001) Substance P. Int J Biochem Cell Biol 33: 355-376.
Hata K, Takebayashi Y, Akiba S, Fujiwara R, Iida K, Nakayama K, Fukumoto M, and Miyazaki K (2000) Expression of the adrenomedullin gene in epithelial ovarian cancer. Mol Hum Reprod 6: 867-872.
Heeschen C, Aicher A, Lehmann R, Fichtlscherer S, Vasa M, Urbich C, Mildner-Rihm C, Martin H, Zeiher AM, and Dimmeler S (2003) Erythropoietin is a potent physiologic stimulus for endothelial progenitor cell mobilization. Blood 102: 1340-1346.
Henke M, Laszig R, Rube C, Schafer U, Haase KD, Schlcher B, Mose S, Beer KT, Burger U, Dougherty C, et al. (2003) Erythropoietin to treat head and neck cancer patients with anaemia undergoing radiotherapy: randomised, double-blind, placebo-controlled trial. Lancet 362: 1255-1260.[CrossRef][Medline]
Hinson JP, Kapas S, and Smith DM (2000) Adrenomedullin a multifunctional regulatory peptide. Endocr Rev 21: 138-167.
Hiromatsu Y and Toda S (2003) Mast cells and angiogenesis. Microsc Res Tech 60: 64-69.[CrossRef][Medline]
Hirschi KK, Rohovsky SA, and D'Amore PA (1998) PDGF, TGF-, and heterotypic cell-cell interactions mediate endothelial cell-induced recruitment of 10T1/2 cells and their differentiation to a smooth muscle fate. J Cell Biol 141: 805-814.
Hoeben A, Landuyt B, Highley MS, Wildiers H, Van Oosterom AT, and De Bruijn EA (2004) Vascular endothelial growth factor and angiogenesis. Pharmacol Rev 56: 549-580.
Hu D, Hiley CR, and Fan TP (1996) Comparative studies of the angiogenic activity of vasoactive intestinal peptide, endothelins-1 and -3 and angiotensin II in a rat sponge model. Br J Pharmacol 117: 545-551.[Medline]
Hug C, Wang J, Ahmad NS, Bogan JS, Tsao TS, and Lodish HF (2004) T-cadherin is a receptor for hexameric and high molecular-weight forms of Acrp30/adiponectin. Proc Natl Acad Sci U S A 101: 10308-10313.
Hültner L and Ehrenreich H (2005) Mast cells and endothelin-1: a life-saving biological liason? Trends Immunol 26: 235-238.[CrossRef][Medline]
Iimuro S, Shindo T, Moriyama N, Amaki T, Niu P, Takeda N, Iwata H, Zhang Y, Ebihara A, and Nagai R (2004) Angiogenic effects of adrenomedullin in ischemia and tumor growth. Circ Res 95: 415-423.
Iruela-Arispe ML, Bornstein P, and Sage H (1991) Thrombospondin exerts an antiangiogenic effect on cord formation by endothelial cells in vitro. Proc Natl Acad Sci U S A 88: 5026-5030.
Itoh H, Pratt RE, and Dzau VJ (1992) Atrial natriuretic peptide as a novel antigrowth factor of endothelial cells. Hypertension 19: 758-761.
Ivanov D, Philippova M, Allenspach R, Erne P, and Resink T (2004) T-cadherin upregulation correlates with cell-cycle progression and promotes proliferation of vascular cells. Cardiovasc Res 64: 132-143.
Iwase T, Nagaya N, Fujii T, Itoh T, Ishibashi-Ueda H, Yamagishi M, Miyatake K, Matsumoto T, Kitamura S, and Kangawa K (2005) Adrenomedullin enhances angiogenic potency of bone marrow transplantation in a rat model of hindlimb ischemia. Circulation 111: 356-362.
Jaquet K, Krause K, Tawakol-Khodai M, Geidel S, and Kuck KH (2002) Erythropoietin and VEGF exhibit equal angiogenic potential. Microvasc Res 64: 326-333.[CrossRef][Medline]
Jelkmann W (2004) Molecular biology of erythropoietin. Intern Med 43: 646-659.
Jimenez N, Abasolo I, Jongsma J, Calvo A, Garayoa M, Van der Kwast TH, Van Steenbrugge GJ, and Montuenga LM (2003) Androgen-independent expression of adrenomedullin and peptidylglycine -amidating monooxigenase in human prostatic carcinomas. Mol Carcinogen 38: 14-24.[CrossRef][Medline]
Julián M, Cacho M, García MA, Martin-Santamaria S, De Pascual-Teresa B, Ramos A, Martínez A, and Cuttitta F (2005) Adrenomedullin: a new target for the design of small molecule modulators with promising pharmacological activities. Eur J Med Chem 40: 737-750.[CrossRef][Medline]
Kadowaki T and Yamauchi T (2005) Adiponectin and adiponectin receptors. Endocr Rev 26: 439-451.
Kamohara M, Matsuo A, Takasaki J, Kohda M, Matsumoto M, Matsumoto SI, Soga T, Hiyama H, Kobori M, and Katou M (2005) Identification of MrgX2 and a human G protein-coupled receptor for proadrenomedullin N-terminal peptide. Biochem Biophys Res Commun 330: 1146-1152.[CrossRef][Medline]
Kandel J, Bossy-Wetzel E, Raduvanyi F, Kalgsbrun M, Folkman J, and Hanahan D (1991) Neovascularization is associated with a switch to export of FGF-2 in the multistep development of fibrosarcoma. Cell 66: 1095-1104.[CrossRef][Medline]
Karvonen MK, Valkonen VP, Lakka TA, Salonen R, Koulu M, Pesonen U, Tuomainen TP, Kauhanen J, Nyyssönen K, Lakka HM, et al. (2001) Leucine 7 to proline 7 polymorphism in the preproneuropeptide Y is associated with the progression of carotid atherosclerosis, blood pressure and serum lipids in Finnish men. Atherosclerosis 159: 145-151.[CrossRef][Medline]
Kato J, Tsuruda T, Kita T, Kitamura K, and Eto T (2005) Adrenomedullin: a protective factor for blood vessels. Arterioscler Thromb Vasc Biol 25: 2480-2487.
Kedzierski RM and Yanagisawa M (2001) Endothelin system: the double-edged sword in health and disease. Annu Rev Pharmacol 41: 851-876.[CrossRef][Medline]
Kim W, Moon SO, Lee S, Sung MJ, Kim SH, and Park SK (2003a) Adrenomedullin reduces VEGF-induced endothelial adhesion molecules and adhesiveness through a phosphatidylinositol 3'-kinase pathway. Arterioscler Thromb Vasc Biol 23: 1377-1383.
Kim W, Moon SO, Sung MJ, Kim SH, Lee SO, So JN, and Park SK (2003b) Angiogenic role of adrenomedullin through activation of Akt mitogen-activated protein kinase, and focal adhesion kinase in endothelial cells. FASEB J 13: 1937-1939.
Kim YM, Jang JW, Lee OH, Yeaon J, Choi EY, Kim KW, Lee ST, and Kwon YG (2000) Endostatin inhibits endothelial and tumor cellular invasion by blocking the activation and catalytic activity of matrix metalloproteinase. Cancer Res 60: 5410-5413.
Kitlinska J (2007) Neuropeptide Y (NPY) in neuroblastoma: effect on growth and vascularization. Peptides 28: 405-412.[CrossRef][Medline]
Kitlinska J, Lee EW, Movafagh S, Pons J, and Zukowska Z (2002) Neuropeptide Y-induced angiogenesis in aging. Peptides 23: 71-77.[CrossRef][Medline]
Kobashi C, Urakaze M, Kishida M, Kibayashi E, Kobayashi H, Kihara S, Funahashi T, Takata M, Temaru R, Sato A, et al. (2005) Adiponectin inhibits endothelial synthesis of interleukin-8. Circ Res 97: 1245-1252.
Kobayashi H, Ouchi N, Kihara S, Walsh K, Kumada M, Abe Y, Funahashi T, and Matsuzawa Y (2004) Selective suppression of endothelial cell apoptosis by the high molecular weight form of adiponectin. Circ Res 94: 27-31.[CrossRef]
Kojima M, Hosoda H, Matsuo H, and Kangawa K (2001) Ghrelin: discovery of the natural endogenous ligand for the growth hormone secretagogue receptor. Trends Endocrinol Metab 12: 118-122.[CrossRef][Medline]
Kojima M and Kangawa K (2005) Ghrelin: structure and function. Physiol Rev 85: 495-522.
Koury MJ (2005) Erythropoietin: the story of hypoxia and a finely regulated hematopoietic hormone. Exp Hematol 33: 1263-1270.[CrossRef][Medline]
Kuhlmann CRW, Most AK, Li F, Munz BM, Schaefer CA, Walther S, Raedle-Hurst T, Waldecker B, Piper HM, Tillmanns H, et al. (2005) Endothelin-1 induced proliferation of human endothelial cells depends on activation of K+ channels and Ca2+ influx. Acta Physiol Scand 183: 161-169.[CrossRef][Medline]
Kumada M, Kihara S, Sumitsuji S, Kawamoto T, Matsumoto S, Ouchi N, Arita Y, Okamoto Y, Shimomura I, Hiraoka H, et al. (2003) Association of hypoadiponectinemia with coronary artery disease in men. Arterioscler Thromb Vasc Biol 23: 85-89.
Kuo LE and Zukowska Z (2007) Stress, NPY and vascular remodeling: implications for stress-related diseases. Peptides 28: 435-440.[CrossRef][Medline]
Kusaka Y, Kelly RA, Williams GH, and Kifor I (2000) Coronary microvascular endothelial cells cosecrete angiotensin II and endothelin-1 via a regulated pathway. Am J Physiol 279: H1087-H1096.
Lawler J (2002) Thrombospondin-1 as an endogenous inhibitor of angiogenesis and tumor growth. J Cell Mol Med 6: 1-12.[Medline]
Le Noble FAC, Hekking JWM, Van Straaten HWM, Slaaf DW, and Struyker-Boudier HAJ (1991) Angiotensin II stimulates angiogenesis in the chorioallantoic membrane of the chick embryo. Eur J Pharmacol 195: 3005-3006.
Lee EW, Grant DS, Movafagh S, and Zukowska Z (2003) Impaired angiogenesis in neuropeptide Y (NPY)-Y2 receptor knockout mice. Peptides 24: 99-106.[CrossRef][Medline]
Levéen P, Pekny M, Gebre-Medhin S, Swolin B, Larsson E, and Betsholtz C (1994) Mice deficient for PDGF-B show renal, cardiovascular and hematological abnormalities. Gene Dev 8: 1875-1887.
Levin ER, Gardner DG, and Samson WK (1998) Natriuretic peptides. N Engl J Med 339: 321-328.
Leyland-Jones B (2003) Breast cancer trial with erythropoietin terminated unexpectedly. Lancet Oncol 4: 459-460.[CrossRef][Medline]
Li J, Zhang YP, and Kirsner RS (2003a) Angiogenesis in wound repair: angiogenic growth factor and the extracellular matrix. Microsc Res Tech 60: 107-114.[CrossRef][Medline]
Li L, Lee EW, Ji H, and Zukowska Z (2003b) Neuropeptide Y-induced acceleration of postangioplasty occlusion of rat carotid artery. Arterioscler Thromb Vasc Biol 23: 1204-1210.
Li Z, Takeuchi S, Otani T, and Maruo T (2001) Implications of adrenomedullin expression in the invasion of squamous cell carcinoma of the uterine cervix. Int J Clin Oncol 6: 263-270.[CrossRef][Medline]
Lindahl P, Johansson BR, Levéen P, and Betsholtz C (1997) Pericyte loss and microaneurysm formation in PDGF-B deficient mice. Science 277: 242-245.
López J and Martínez A (2002) Cell and molecular biology of the multifunctional peptide adrenomedullin. Int Rev Cytol 221: 1-92.[Medline]
Mahmud DL, Amlak M, Deb DK, Platanias LC, Uddin S, and Wickrema A (2002) Phosphorylation of forkhead transcription factors by erythropoietin and stem cell factor prevents acetylation and their interaction with coactivator p300 in erythroid progenitor cells. Oncogene 21: 1556-1562.[CrossRef][Medline]
Maisonpierre PC, Suri C, Jones PF, Bartunkova S, Wiegand SJ, Radziejewski C, Compton D, McClain J, Aldrich TH, Papadopoulos N, et al. (1997) Angiopoietin-2, a natural antagonist for Tie2 that disrupts in vivo angiogenesis. Science 277: 55-60.
Martínez A, Bengoechea JA, and Cuttitta F (2006) Molecular evolution of proadrenomedullin N-terminal 20 peptide (PAMP): evidence for gene co-option. Endocrinology 147: 3457-3461.
Martínez A, Vos M, Guedez L, Kaur G, Chen Z, Garayoa M, Pio R, Moody T, Stetler-Stevenson WG, Kleinman HK, et al. (2002) The effects of adrenomedullin overexpression in breast tumor cells. J Natl Cancer Inst 94: 1226-1237.
Martínez A, Zudaire E, Portal-Nuñez, Guedez L, Libutti SK, Stetler-Stevenson WG, and Cuttitta F (2004) Proadrenomedullin NH2-terminal 20 peptide is a potent angiogenic factor, and its inhibition results in reduction of tumor growth. Cancer Res 64: 6489-6494.
Masuzaki H, Ogawa Y, Sagawa N, Hosoda K, Matsumoto T, Mise H, Nishimura H, Yoshimasa Y, Tanaka I, Mori T, et al. (1997) Nonadipose tissue production of leptin: leptin as a novel placenta-derived hormone in humans. Nat Med 3: 1029-1033.[CrossRef][Medline]
Matsusaka T and Ichikawa I (1997) Biological functions of angiotensin and its receptor. Annu Rev Physiol 59: 375-412.
Matsuura A, Yamochi W, Hirata K, Kawashima S, and Yokoyama M (1998) Stimulatory interaction between vascular endothelial growth factor and endothelin-1 on each gene expression. Hypertension 32: 89-95.
Maurer M, Wedemeyer J, Metz M, Piliponsky AM, Weller K, Chatterjea D, Clouthier DE, Yanagisawa MM, Tsai M, and Galli SJ (2004) Mast cells promote homeostasis by limiting endothelin-1-induced toxicity. Nature 432: 512-516.[CrossRef][Medline]
Mazzocchi G, Malendowicz LK, Ziolkowska A, Spinazzi R, Rebuffat P, Aragona F, Ferrazzi E, Parnigotto PP, and Nussdorfer GG (2004) Adrenomedullin (AM) and AM receptor type-2 expression is up-regulated in prostate carcinomas (PC), and AM stimulates in vitro growth of a PC-derived cell line by enhancing proliferation and decreasing apoptosis rates. Int J Oncol 25: 1781-1787.[Medline]
Mentlein R, Eichler O, Forstreuter F, and Held-Feindt J (2001) Somatostatin inhibits the production of vascular endothelial growth factor in human glioma cells. Int J Cancer 92: 545-550.[CrossRef][Medline]
Michel MC, Beck-Sickinger A, Cox H, Doods HN, Herzog H, Larhammar D, Quirion R, Schwartz T, and Westfall T (1998) XVI. International Union of Pharmacology recommendations for the nomenclature of neuropeptide Y, peptide YY, and pancreatic polypeptide receptors. Pharmacol Rev 50: 143-150.
Mignatti P and Rifkin DB (1993) Biology and biochemistry of proteinases in tumor invasion. Physiol Rev 73: 161-195.
Miyashita K, Itoh H, Arai H, Suganami T, Sawada N, Fukunaga Y, Sone M, Yamahara K, Yurugi-Kobayashi T, Park K, et al. (2006) The neuroprotective and vasculo-neuro-regenerative roles of adrenomedullin in ischemic brain and its therapeutic potential. Endocrinology 147: 1642-1653.
Miyashita K, Itoh H, Sawada N, Fukunaga Y, Sone M, Yamahara K, Yurugi-Kobayashi T, Park K, and Nakao K (2003) Adrenomedullin provokes endothelial Akt activation and promotes vascular regeneration both in vitro and in vivo. FEBS Lett 544: 86-92.[CrossRef][Medline]
Mohamed-Ali V, Pinkney JH, and Coppack SW (1998) Adipose tissue as an endocrine and paracrine organ. Int J Obes Relat Metab Disord 22: 1145-1158.[CrossRef][Medline]
Molet S, Furukawa K, Maghazechi A, Hamid Q, and Giaid A (2000) Chemokine and cytokine-induced expression of endothelin-1 and endothelin converting enzyme-1 in endothelial cells. J Allergy Clin Immunol 105: 333-338.[CrossRef][Medline]
Moody TW, Leyton J, Casibang M, Pisegna J, and Jensen RT (2002) PACAP-27 tyrosine phosphorylates mitogen activated protein kinase and increases VEGF mRNAs in human lung cancer cells. Regul Pept 109: 135-140.[CrossRef][Medline]
Morbidelli L, Orlando C, Maggi CA, Ledda F, and Ziche M (1995) Proliferation and migration of endothelial cells is promoted by endothelins via activation of ETB receptors. Am J Physiol 269: H685-H695.
Movafagh S, Hobson JP, Spiegel S, Kleinman HK, and Zukowska Z (2006) Neuropeptide Y induces migration, proliferation, and tube formation of endothelial cells bimodally via Y1, Y2, and Y5 receptors. FASEB J 20: 1327-1337.
Mu H, Ohashi R, Yan S, Chai H, Yang H, Lin P, Yao Q, and Chen C (2006) Adipokine resistin promotes in vitro angiogenesis of human endothelial cells. Cardiovasc Res 70: 146-157.
Müller-Ehmsen J, Schmidt A, Krausgrill B, Schwinger RHG, and Bloch W (2006) Role of erythropoietin for angiogenesis and vasculogenesis: from embryonic development through adulthood. Am J Physiol 290: H331-H340.
Nagaya N, Mori H, Mutokami S, Kangawa K, and Kitamura S (2005) Adrenomedullin: angiogenesis and gene therapy. Am J Physiol 288: R1432-R1437.
Nakayama M, Takahashi K, Murakami O, Shirato K, and Shibahara S (1998) Induction of adrenomedullin by hypoxia and cobalt chloride in human colorectal carcinoma cells. Biochem Biophys Res Commun 243: 514-517.[CrossRef][Medline]
Nguyen SV and Claycomb WC (1999) Hypoxia regulates the expression of adrenomedullin and HIF-1 genes in cultured HL-1 cardiomyocytes. Biochem Biophys Res Commun 265: 382-386.[CrossRef][Medline]
Nikitenko LL, Fox SB, Kekoe S, Rees MCP, and Bicknell R (2006) Adrenomedullin and tumor angiogenesis. Br J Cancer 94: 1-7.[CrossRef][Medline]
Nikitenko LL, Smith DM, Hague S, Wilson CR, Bicknell R, and Rees MCP (2002) Adrenomedullin and the microvasculature. Trends Pharmacol Sci 23: 101-103.[CrossRef][Medline]
Niskanen L, Karvonen MK, Valve R, Koulu M, Pesonen U, Mercuri M, Rauramaa R, Töyry J, Laakso M, and Uusitupa MIJ (2000) Leucine 7 to proline 7 polymorphism in the neuropeptide Y gene is associated with enhanced carotid atherosclerosis in elderly patients with type 2 diabetes and control subjects. J Clin Endocrinol Metab 85: 2266-2269.
Noiri E, Hu Y, Bahou WF, Keese CR, Giaever I, and Goligorsky MS (1997) Permissive role of nitric oxide in endothelin-induced migration of endothelial cells. J Biol Chem 272: 1747-1752.
Noiri E, Lee E, Testa J, Quigley J, Colflesh D, Keese CR, Giaever I, and Goligorsky MS (1998) Podokinesis in endothelial cell migration: role of NO. Am J Physiol 274: C236-C244.[Medline]
Nothacker HP, Wang Z, Zeng H, Mahata SK, O'Connor DT, and Civelli O (2005) Proadrenomedullin N-terminal peptide and corticostatin activation of MrgX2 receptor is based on a common structural motif. Eur J Pharmacol 519: 191-193.[CrossRef][Medline]
Nussdorfer GG (2001) Proadrenomedullin-derived peptides in the paracrine control of the hypothalamo-pituitary-adrenal axis. Int Rev Cytol 206: 249-284.[Medline]
Nussdorfer GG and Malendowicz LK (1998) Role of tachykinins in the regulation of the hypothalamo-pituitary-adrenal axis. Peptides 19: 949-968.[CrossRef][Medline]
Nussdorfer GG, Rossi GP, Malendowicz LK, and Mazzocchi G (1999) Autocrine-paracrine endothelin system in the physiology and pathology of steroid-secreting tissues. Pharmacol Rev 51: 403-438.
Oehler MK, Fischer DC, Orlowska-Volk M, Herrie F, Kiebach DG, Rees MC, and Bicknell R (2003) Tissue and plasma expression of the angiogenic peptide adrenomedullin in the breast cancer. Br J Cancer 89: 1927-1933.[CrossRef][Medline]
Oehler MK, Hague S, Reese MC, and Bicknell R (2002) Adrenomedullin promotes formation of xenografted endometrial tumors by stimulation of autocrine growth and angiogenesis. Oncogene 21: 2815-2821.[CrossRef][Medline]
Oehler MK, Norbury C, Hague S, Rees MC, and Bicknell R (2001) Adrenomedullin inhibits hypoxic cell death by upregulation of Bcl-2 in endometrial cancer cells: a possible promotion mechanism for tumour growth. Oncogene 20: 2937-2945.[CrossRef][Medline]
Okamoto Y, Kihara S, Ouchi N, Nishida M, Arita Y, Kumada M, Ohashi K, Sakai N, Shimomura I, Kobayashi H, et al. (2002) Adiponectin reduces atherosclerosis in apolipoprotein E-deficient mice. Circulation 106: 2767-2770.
Okuda Y, Tsurumaru K, Suzuki S, Miyauchi T, Asano M, Hong Y, Sone H, Fujita R, Mizutani M, Kawakami Y, et al. (1998) Hypoxia and endothelin-1 induce VEGF production in human vascular smooth muscle cells. Life Sci 63: 477-484.[CrossRef][Medline]
Olias G, Viollet C, Kusserow H, Epelbaum J, and Meyerhof W (2004) Regulation and function of somatostatin receptors. J Neurochem 89: 1057-1091.[CrossRef][Medline]
O'Reilly MS, Boehm T, Shing Y, Fukai N, Vasios G, Lane WS, Flynn E, Birkhead JR, Olsen BR, and Folkman J (1997) Endostatin: an endogenous inhibitor of angiogenesis and tumor growth. Cell 88: 277-285.[CrossRef][Medline]
O'Reilly MS, Holmgren L, Chen C, and Folkman J (1996) Angiostatin induces and sustains dormancy of human primary tumors in mice. Nat Med 2: 689-692.[CrossRef][Medline]
O'Reilly MS, Holmgren L, Shing Y, Chen C, Rosenthal RA, Moses M, Lane WS, Cao Y, Sage EH, and Folkman J (1994) Angiostatin: a novel angiogenesis inhibitor that mediates the suppression of metastases by a Lewis lung carcinoma. Cell 79: 315-328.[CrossRef][Medline]
Ortega S, Ittmann SH, Tsang M, Ehrlich M, and Basilico C (1998) Neuronal defects and delayed wound healing in mice lacking fibroblast growth factor-2. Proc Natl Acad Sci U S A 95: 5672-5677.
Otani A, Takagi H, Suzuma K, and Honda Y (1998) Angiotensin II potentiates vascular endothelial growth factor-induced angiogenic activity in retinal microcapillary endothelial cells. Circ Res 82: 619-628.
Ouchi N, Kobayashi H, Kihara S, Kumada M, Sato K, Inoue T, Funahashi T, and Walsh K (2004) Adiponectin stimulates angiogenesis by promoting cross-talk between AMP-activated protein kinase and Akt signaling in endothelial cells. J Biol Chem 279: 1304-1309.
Parsa CJ, Matsumoto A, Kim J, Riel RU, Pascal LS, Walton GB, Thompson RB, Petrofski JA, Annex BH, Stamler JS, et al. (2003) A novel protective effect of erythropoietin in the infarcted heart. J Clin Invest 112: 999-1007.[CrossRef][Medline]
Patel Y (1999) Somatostatin and its receptor family. Front Neuroendocrinol 20: 157-198.[CrossRef][Medline]
Pedram A, Hu RM, and Levin ER (1997a) Vasoactive peptides modulate vascular endothelial growth factor production and endothelial cell proliferation and invasion. J Biol Chem 272: 17097-17103.
Pedram A, Razandi M, Hu RM, and Levin ER (1997b) Vasoactive peptides modulate vascular endothelial cell growth factor production and endothelial cell proliferation and invasion. J Biol Chem 272: 17097-17103.
Pedram A, Razandi M, and Levin ER (2001) Natriuretic peptides suppress vascular endothelial cell growth factor signaling to angiogenesis. Endocrinology 142: 1578-1586.
Pepper MS (1997) Manipulating angiogenesis: from basic science to the bedside. Arterioscler Thromb Vasc Biol 17: 605-619.
Pepper MS, Vassalli JD, Wilks JW, Schweigerer L, Orci L, and Montesano R (1994) Modulation of bovine microvascular endothelial cell proteolytic properties by inhibition of angiogenesis. J Cell Biochem 55: 419-434.[CrossRef][Medline]
Poyner DR, Sexton PM, Marshall I, Smith DM, Quirion R, Born W, Muff R, Fischer JA, and Foord SM (2002) International Union of Pharmacology. XXXII. The mammalian calcitonin gene-related peptides, adrenomedullin, amylin, and calcitonin receptors. Pharmacol Rev 54: 233-246.
Presta M, Dell'Era P, Mitola S, Moroni E, Ronca R, and Rusnati M (2005) Fibroblast growth factor/fibroblast growth factor receptor system in angiogenesis. Cytokine Growth Factor Rev 16: 159-178.[CrossRef][Medline]
Reilly MP, Lehrke M, Wolfe ML, Rohatgi A, Lazar MA, and Rader DJ (2005) Resistin is an inflammatory marker of atherosclerosis in humans. Circulation 111: 932-939.
Ren B, Yee KO, Lawler J and Khosravi-Far R (2006) Regulation of tumor angiogenesis by thrombospondin-1. Biochim Biophys Acta 1765: 178-188.[Medline]
Rhodin JAG and Fujita H (1989) Capillary growth in mesentery of normal young rats. Intravital video and electron microscope analyses. J Submicrosc Cytol Pathol 21: 1-34.[Medline]
Ribatti D (2005) The crucial role of vascular permeability factor/vascular endothelial growth factor in angiogenesis: a historical review. Br J Haematol 128: 303-309.[CrossRef][Medline]
Ribatti D (2006) Genetic and epigenetic mechanisms in the early development of the vascular system. J Anat 208: 139-152.[CrossRef][Medline]
Ribatti D, Guidolin D, Conconi MT, Nico B, Baiguera S, Parnigotto PP, Vacca A, and Nussdorfer GG (2003a) Vinblastine inhibits the angiogenic response induced by adrenomedullin in vitro and in vivo. Oncogene 22: 6458-6461.[CrossRef][Medline]
Ribatti D, Nico B, Belloni AS, Vacca A, Roncali L, and Nussdorfer GG (2001) Angiogenic activity of leptin in the chick embryo chorioallantoic membrane is in part mediated by endogenous fibroblast growth factor-2. Int J Mol Med 8: 265-268.[Medline]
Ribatti D, Nico B, Crivellato E, Roccaro AM, and Vacca A (2007) The history of the angiogenic switch concept. Leukemia 21: 44-52.[CrossRef][Medline]
Ribatti D, Nico B, Spinazzi R, Vacca A, and Nussdorfer GG (2005) The role of adrenomedullin in angiogenesis. Peptides 26: 1670-1675.[CrossRef][Medline]
Ribatti D, Nico B, Vacca A, Roncali L, and Dammacco F (2002a) Endothelial cell heterogeneity and organ specificity. J Hematother Stem Cell Res 11: 81-90.[CrossRef][Medline]
Ribatti D, Presta M, Vacca A, Ria R, Giuliani R, Dell'Era P, Nico B, Roncali L, and Dammacco F (1999a) Human erythropoietin induces a proangiogenic phenotype in cultured endothelial cells and stimulates neovascularization in vivo. Blood 93: 2627-2636.
Ribatti D, Scavelli C, Roccaro AM, Crivellato E, Nico B, and Vacca A (2004) Hematopoietic cancer and angiogenesis. Stem Cell Dev 13: 484-495.[CrossRef]
Ribatti D, Vacca A, and Dammacco F (1999b) The role of vascular phase in solid tumor growth: a historical review. Neoplasia 1: 293-302.[CrossRef][Medline]
Ribatti D, Vacca A, and Presta M (2002b) The discovery of angiogenic factors: a historical review. Gen Pharmacol 35: 227-231.
Ribatti D, Vacca A, Roccaro AM, Crivellato E, and Presta M (2003b) Erythropoietin as an angiogenic factor. Eur J Clin Invest 33: 891-896.[CrossRef][Medline]
Richard DE, Berra E, and Pouyssegur J (2000) Nonhypoxic pathway mediates the induction of hypoxia-inducible factor 1 in vascular smooth muscle cells. J Biol Chem 275: 26765-26771.
Richardson JD and Vasko MR (2002) Cellular mechanisms of neurogenic inflammation. J Pharmacol Exp Ther 302: 839-845.
Risau W (1997) Mechanisms of angiogenesis. Nature 386: 671-674.[CrossRef][Medline]
Rosanò L, Varmi M, Salani D, Di Castro V, Spinella F, Natali PG, and Bagnato A (2001) Endothelin-1 induces proteinase activation and invasiveness of ovarian carcinoma cells. Cancer Res 61: 8340-8346.
Rossert J and Eckardt KU (2005) Erythropoietin receptors: their role beyond erythropoiesis. Nephrol Dial Transplant 20: 1025-1028.
Rossi GP, Seccia TM, and Nussdorfer GG (2001) Reciprocal regulation of endothelin-1 and nitric oxide: relevance in the physiology and pathology of the cardiovascular system. Int Rev Cytol 209: 241-272.[Medline]
Rubanyi GM and Polokoff MA (1994) Endothelins: molecular biology biochemistry, pharmacology, physiology, and pathophysiology. Pharmacol Rev 46: 325-415.[Medline]
Rück A, Gustafsson T, Norrbom J, Nowak J, Källner G, Söderberg M, Sylven C, and Drvota V (2004) ANP and BNP but not VEGF are regionally overexpressed in ischemic human myocardium. Biochem Biophys Res Commun 322: 287-291.[CrossRef][Medline]
Rüegg C, Hasmim M, Lejeune FJ, and Alghisi GC (2006) Antiangiogenic peptides and proteins: from experimental tools to clinical drugs. Biochim Biophys Acta 1765: 155-177.[Medline]
Rusnati M and Presta M (1996) Interaction of angiogenic basic fibroblast growth factor with endothelial cell heparan sulfate proteoglycans. Int J Clin Lab Res 26: 15-23.[Medline]
Saijonmaa O, Nyman T, and Fyhrquist F (1992) Endothelin-1 stimulates its own synthesis in human endothelial cells. Biochem Biophys Res Commun 188: 286-291.[CrossRef][Medline]
Salani D, Di Castro V, Nicotra MR, Rosanò L, Tecce R, Venuti A, Natali PG, and Bagnato A (2000a) Role of endothelin-1 in neovascularization of ovarian carcinoma. Am J Pathol 157: 1537-1547.
Salani D, Taraboletti G, Rosanò L, Di Castro V, Borsotti P, Giavazzi R, and Bagnato A (2000b) Endothelin-1 induces an angiogenic phenotype in cultured endothelial cells and stimulates neovascularization in vivo. Am J Pathol 157: 1703-1711.
Samson WK (1999) Adrenomedullin and the control of fluid and electrolyte homeostasis. Annu Rev Physiol 61: 363-390.[CrossRef][Medline]
Sasaki K, Murohara T, Ikeda H, Sugaya T, Shimada T, Shintani S, and Imaizumi T (2002) Evidence for the importance of angiotensin II type 1 receptor in ischemia-induced angiogenesis. J Clin Invest 109: 603-611.[CrossRef][Medline]
Schwarz N, Renshaw D, Kapas S, and Hinson JP (2006) Adrenomedullin increases the expression of calcitonin-like receptor and receptor activity modifying protein 2 mRNA in human microvascular endothelial cells. J Endocrinol 190: 505-514.
Seegers HC, Hood VC, Kidd BL, Cruwys SC, and Walsh DA (2003) Enhancement of angiogenesis by endogenous substance P release and neurokinin-1 receptors during neurogenic inflammation. J Pharmacol Exp Ther 306: 8-12.
Shah NM, Groves AK, and Anderson DJ (1996) Alternative neural crest cell fates are instructively promoted by TGF superfamily members. Cell 85: 331-343.[CrossRef][Medline]
Shibata R, Ouchi N, Kihara S, Sato K, Funahashi T, and Walsh K (2004) Adiponectin stimulates angiogenesis in response to tissue ischemia through stimulation of AMP-activated protein kinase signaling. J Biol Chem 279: 28670-28674.
Shichiri M, Kato H, Marumo F, and Hirata Y (1997) Endothelin-1 as an autocrine/paracrine apoptosis survival factor for endothelial cells. Hypertension 30: 1198-1203.
Shichiri M, Yokokura M, Marumo F, and Hirata Y (2000) Endothelin-1 inhibits apoptosis of vascular smooth muscle cells induced by nitric oxide and serum-deprivation via MAP kinase pathway. Arterioscler Thromb Vasc Biol 20: 989-997.
Shigeri Y and Fujimoto M (1993) Neuropeptide Y stimulates DNA synthesis in vascular smooth muscle cells. Neurosci Lett 149: 19-21.[CrossRef][Medline]
Shimizu T, Okamoto H, Chiba S, Matsui Y, Sugawara T, Akino M, Nan J, Kumamoto H, Onozuka H, Mikami T, et al. (2003) VEGF-mediated angiogenesis is impaired by angiotensin type 1 receptor blockade in cardiomyopathic hamster hearts. Cardiovasc Res 58: 203-212.
Shindo T, Kurihara Y, Nishimatsu H, Moriyama N, Kakoki M, Wang Y, Imai Y, Ebihara A, Kuwaki T, Ju KH, et al. (2001) Vascular abnormalities and elevated blood pressure in mice lacking adrenomedullin gene. Circulation 104: 1964-1971.
Sierra-Honigmann MR, Nath AK, Murakami C, Garcia-Cardena G, Papapetropoulos A, Sessa WC, Madge LA, Schechner JS, Schwabb MB, Polverini PJ, et al. (1998) Biological action of leptin as an angiogenic factor. Science 281: 1683-1686.
Silberbach M and Roberts CR Jr (2001) Natriuretic peptide signaling. Molecular and cellular pathways to growth regulation. Cell Signal 13: 221-231.[CrossRef][Medline]
Silvestre JS, Tamarat R, Sebonmatsu T, Icchiki T, Ebrahimian T, Iglarz M, Besnard S, Durier M, Inagami T, and Levy BI (2002) Antiangiogenic effect of angiotensin II type 2 receptor in ischemia-induced angiogenesis in mice hindlimb. Circ Res 90: 1072-1079.
Simons M (2004) Integrative signaling in angiogenesis. Mol Cell Biochem 264: 99-102.[CrossRef][Medline]
Spinazzi R, Albertin G, Nico B, Guidolin D, Di Liddo R, Rossi GP, Ribatti D, and Nussdorfer GG (2006) Urotensin II and its receptor (UT-R) are expressed in rat brain endothelial cells and UII via UT-R stimulates angiogenesis in vivo and in vitro. Int J Mol Med 18: 1107-1112.[Medline]
Spinazzi R, Andreis PG, and Nussdorfer GG (2005) Neuropeptide-Y and Y-receptors in the autocrine-paracrine regulation of adrenal gland under physiological and pathophysiological conditions. Int J Mol Med 15: 3-13.[Medline]
Spinella F, Rosanò L, Di Castro V, Natali PG, and Bagnato A (2002) Endothelin-1 induces vascular endothelial growth factor by increasing hypoxia-inducible factor-1 in ovarian carcinoma cells. J Biol Chem 277: 27850-27855.
Spinella F, Rosanò L, Di Castro V, Natali PG, and Bagnato A (2004) Endothelin-1-induced prostaglandin E2-EP2,EP4 signaling regulates vascular endothelial growth factor production and ovarian carcinoma cell invasion. J Biol Chem 279: 46700-46705.
Steppan CM, Bailey ST, Bhat S, Brown EJ, Banerjee RR, Wright CM, Patel HR, Ahima RS, and Lazar MA (2001) The hormone resistin links obesity to diabetes. Nature 409: 307-312.[CrossRef][Medline]
Stiles JD, Ostrow PT, Balos LL, Greenberg SJ, Plunkett R, Grand W, and Heffner RR Jr (1997) Correlation of endothelin-1 and transforming growth factor 1 with malignancy and vascularity in human gliomas. J Neuropathol Exp Neurol 56: 435-439.[Medline]
Stoll M, Steckelings UM, Paul M, Bottari SP, Metzger R, and Unger T (1995) The angiotensin AT2-receptor mediates inhibition of cell proliferation in coronary endothelial cells. J Clin Invest 95: 651-657.[Medline]
Suhardja A and Hoffman H (2003) Role of growth factors and their receptors in proliferation of microvascular endothelial cells. Microsc Res Tech 60: 70-75.[CrossRef][Medline]
Sweeney G (2002) Leptin signaling. Cell Signal 14: 655-663.[CrossRef][Medline]
Taddei L, Chiarugi P, Brogelli L, Cirri P, Magnelli L, Raugei G, Ziche M, Granger HJ, Chiarugi V, and Ramponi G (1999) Inhibitory effect of full-length human endostatin on in vitro angiogenesis. Biochem Biophys Res Commun 263: 340-345.[CrossRef][Medline]
Tait CR and Jones PF (2004) Angiopoietins in tumours: the angiogenic switch. J Pathol 204: 1-10.[CrossRef][Medline]
Taraboletti G, Roberts D, Liotta LA, and Giavazzi R (1990) Platelet thrombospondin modulates endothelial cell adhesion, motility, and growth: a potential angiogenesis regulatory factor. J Cell Biol 111: 765-772.
Thurston G (2003) Role of angiopoietins and Tie receptor tyrosine kinases in angiogenesis and lymphangiogenesis. Cell Tissue Res 314: 61-68.[CrossRef][Medline]
Tokunaga N, Nagaya N, Shirai M, Tanaka E, Ishibashi-Ueda H, Harada-Shiba M, Kanda M, Ito T, Shimizu W, Tabata T, et al. (2004) Adrenomedullin gene transfer induces therapeutic angiogenesis in a rabbit model of chronic hind limb ischemia: benefits of a novel nonviral vector, gelatin. Circulation 109: 526-531.
Touyz RM and Schiffrin EL (2000) Signal transduction mechanisms mediating the physiological and pathophysiological actions of angiotensin II in vascular smooth muscle cells. Pharmacol Rev 52: 639-672.
Tsuruda T, Kato J, Hatakeyama K, Yamashita A, Nakamura K, Imamura T, Kitamura K, Onitsuka T, Asada Y, and Eto T (2006) Adrenomedullin in mast cells of abdominal aortic aneurysm. Cardiovasc Res 70: 158-164.
Turner HE, Harris AL, Melmed S, and Wass JAM (2003) Angiogenesis in endocrine tumors. Endocr Rev 24: 600-632.
Vacca A and Ribatti D (2006) Bone marrow angiogenesis in multiple myeloma. Leukemia 20: 193-199.[CrossRef][Medline]
van der Lely AJ, Tschöp M, Heiman ML, and Ghigo E (2004) Biological, physiological, pathophysiological, and pharmacological aspects of ghrelin. Endocr Rev 25: 426-457.
van Hinsbergh VWM, Engelse MA, and Quax PHA (2006) Pericellular proteases in angiogenesis and vasculogenesis. Arterioscler Thromb Vasc Biol 26: 716-728.
Vaudry D, Gonzales BJ, Basille M, Yon L, Fournier A, and Vaudry H (2000) Pituitary adenylate cyclase-activating polypeptide and its receptors: from structure to function. Pharmacol Rev 52: 269-324.
Verhaar MC, Grahn AY, Van Weerdt AW, Honing ML, Morrison PJ, Yang YP, Padley RJ, and Rabelink TJ (2000) Pharmacokinetics and pharmacodynamic effects of ABT 627, an oral ETA selective endothelin antagonist, in humans. Br J Clin Pharmacol 49: 562-573.[CrossRef][Medline]
Verma S, Li SH, Wang CH, Fedak PWM, Li RK, Weisel RD, and Mickle DAG (2003) Resistin promotes endothelial cell activation: further evidence of adipokine-endothelial interaction. Circulation 108: 736-740.
Vigne P, Marsault R, Breittmayer JP, and Frelin C (1990) Endothelin stimulates phosphatidylinositol hydrolysis and DNA synthesis in brain capillary endothelial cells. Biochem J 266: 415-420.[Medline]
von Tell D, Armulik A, and Betsholtz C (2006) Pericytes and vascular stability. Exp Cell Res 312: 623-629.[CrossRef][Medline]
Walsh DA, Hu DE, Wharton J, Catravas JD, Blake DR, and Fan TP (1997) Sequential development of angiotensin receptors and angiotensin II-converting enzyme during angiogenesis in the rat subcutaneous sponge granuloma. Br J Pharmacol 120: 1302-1311.[CrossRef][Medline]
Walther T, Menrad A, Orzechowski HD, Siemeister G, Paul M, and Schirner M (2003) Differential regulation of in vivo angiogenesis by angiotensin II receptors. FASEB J 17: 2061-2067.
Wang H, Chen Z, and Anderson D (1998) Molecular distinction and angiogenic interaction between embryonic arteries and veins revealed by ephrin-B2 and its receptor Eph-B4. Cell 93: 741-753.[CrossRef][Medline]
Watson JG, Balster DA, Gebhardt BM, O'Dorisio TM, O'Dorisio MS, Espenan GD, Drouant GJ, and Woltering EA (2001) Growing vascular endothelial cells express somatostatin subtype 2 receptors. Br J Cancer 85: 266-272.[CrossRef][Medline]
Williams B, Baker AQ, Gallacher B, and Lodwick D (1995) Angiotensin II increases vascular permeability factor gene expression by human vascular smooth muscle cells. Hypertension 25: 913-917.
Wolf G (2003) Adiponectin: a regulator of energy homeostasis. Nutr Rev 61: 290-292.[CrossRef][Medline]
Wu-Wong JR, Chiou WJ, Dickinson R, and Opgenorth TJ (1997) Endothelin attenuates apoptosis in human smooth muscle cells. Biochem J 328: 733-737.[Medline]
Xia CF, Yin H, Borlongan CV, Chao J, and Chao L (2006) Postischemic infusion of adrenomedullin protects against ischemic stroke by inhibiting apoptosis and promoting angiogenesis. Exp Neurol 197: 521-530.[CrossRef][Medline]
Yamaguchi N, Anand-Apte B, Lee M, Sasaki T, Fukai N, Shapiro R, Que I, Lowi KC, Timpl R, and Olsen BR (1999) Endostatin inhibits VEGF-induced endothelial cell migration and tumor growth independently of zinc binding. EMBO J 18: 4414-4423.[CrossRef][Medline]
Yamashita K (2001) Molecular regulation of the endothelin-1 gene by hypoxia. Contributions of hypoxia-inducible factor-1 activator protein-1, GATA-2 and p300/CBP. J Biol Chem 276: 12645-12653.
Yoshimoto T, Matsushita M, and Hirata Y (2004) Role of urotensin II in peripheral tissues as an autocrine/paracrine growth factor. Peptides 25: 1775-1781.[CrossRef][Medline]
Zhang QX, Magovern C, Mack C, Budenbender K, Ko W, and Rosengart T (1997) Vascular endothelial growth factor is the major angiogenic factor in omentum: mechanism of the omentum-mediated angiogenesis. J Surg Res 67: 147-154.[CrossRef][Medline]
Ziche M, Morbidelli L, Masini E, Amerini S, Granger HJ, Maggi CA, Geppetti P, and Ledda F (1994) Nitric oxide mediates angiogenesis in vivo and endothelial cell growth and migration in vitro promoted by substance P. J Clin Invest 94: 2036-2044.[Medline]
Ziche M, Morbidelli L, Pacini M, Geppetti P, Alessandri G, and Maggi CA (1990) Substance P stimulates neovascularization in vivo and proliferation of cultured endothelial cells. Microvasc Res 40: 264-278.[CrossRef][Medline]
Zudaire E, Martínez A, Garayoa M, Pio R, Kaur G, Woolhiser MR, Metcalfe DD, Hook WA, Siraganian RP, Guise TA, et al. (2006) Adrenomedullin is a cross-talk molecule that regulates tumor and mast cell function during human carcinogenesis. Am J Pathol 168: 280-291.
Zukowska-Grojec Z, Karwatowska-Prokopczuk E, Fisher TA, and Ji H (1998a) Mechanisms of vascular growth promoting effects of neuropeptide Y: role of its inducible receptors. Regul Pept 75/ 76: 231-238.[CrossRef][Medline]
Zukowska-Grojec Z, Karwatowska-Prokopczuk E, Rose W, Rone J, Movafagh S, Ji H, Yeh Y, Chen WT, Kleinman HK, Grouzmann E, et al. (1998b) Neuropeptide Y: a novel angiogenic factor from the sympathetic nerves and endothelium. Circ Res 83: 187-195.
Zukowska-Grojec Z, Pruszczyk P, Colton C, Yao J, Shen GH, Myers AK, and Wahlestedt C (1993) Mitogenic effect of neuropeptide Y in rat vascular smooth muscle cells. Peptides 14: 263-268.[CrossRef][Medline]
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