VEGF-receptor signal transduction

doi:10.1016/S0968-0004(03)00193-2

Trends in Biochemical Sciences

Volume 28, Issue 9, September 2003, Pages 488-494

https://doi.org/10.1016/S0968-0004(03)00193-2 Get rights and content

Abstract

The vascular endothelial growth factor (VEGF) family of ligands and receptors has been the focus of attention in vascular biology for more than a decade. There is now a consensus that the VEGFs are crucial for vascular development and neovascularization in physiological and pathological processes in both embryo and adult. This has facilitated a rapid transition to their use in clinical applications, for example, administration of VEGF ligands to enhance vascularization of ischaemic tissues and, conversely, inhibitors of VEGF-receptor function in anti-angiogenic therapy. More recent data indicate essential roles for the VEGFs in haematopoietic cell function and in lymphangiogenesis.

Section snippets

The VEGFs

VEGF-A, the original VEGF, exists in four different isoforms (comprising 121, 165, 189 and 206 amino acids in humans), which are generated by alternative splicing of a single pre-mRNA species. The region encoding VEGF-A spans ∼14 kb and contains eight exons (Fig. 1). The isoforms differ in their ability to bind to heparan sulfate and extracellular matrix (ECM). VEGF-A₁₂₁, which lacks the region encoded by exons six and seven, does not bind to heparan sulfate and is freely diffusible, whereas

Expression, signal transduction and function of VEGFR-1

VEGFR-1 (also known as Flt-1) is a 180-kDa high-affinity receptor for VEGF-A, VEGF-B and PlGF. It is expressed in vascular endothelial cells and a range of non-endothelial cells including haematopoietic stem cells, macrophages and monocytes (Fig. 2). Vegfr-1^−/− mouse embryos die at day 8.5–9 due to obstruction of vessels by an overgrowth of endothelial cells [11]. The increase in the number of endothelial progenitors in the absence of VEGFR-1 [12] implies a negative regulatory role for the

Expression, signal transduction and function of VEGFR-2

VEGFR-2 (also known as KDR or Flk-1), is a 200–230-kDa high-affinity receptor for VEGF-A, the processed forms of VEGF-C and -D, and VEGF-E. It is expressed in both vascular endothelial and lymphatic endothelial cells; its expression has also been demonstrated in several other cell types such as megakaryocytes and haematopoietic stem cells [30]. Vegfr-2^−/− embryos die by embryonic day 8.5–9.5, exhibiting defects in the development of endothelial and haematopoietic precursors, indicating that the

Expression, signal transduction and function of VEGFR-3

VEGFR-3 (also known as Flt-4) is a 195-kDa high-affinity receptor for VEGF-C and VEGF-D. Distinct features of VEGFR-3 includes cleavage during synthesis within the fifth extracellular immunoglobulin loop; the two regulating polypeptides are kept together by a disulfide bridge [55]. There are two VEGFR-3 splice variants in humans, one short and one long; the latter has a C-terminal extension of 65 amino acids 56, 57 that is created by a retroviral insertion [58]. Mouse embryos lacking expression

Concluding remarks and future perspectives

There has been an intense focus in the past few years on the development of therapies based on modulation of VEGFR function. Gene therapy using VEGF-A to enhance vascularization has been tested in conditions such as cardiovascular diseases and peripheral ischaemia. However, these diseases build up over many decades and the relatively short duration of VEGF expression (e.g. upon adenovirus-mediated delivery) is likely to lead to alleviation of these conditions only temporarily. Moreover,

Acknowledgements

The authors are supported by grants from the Swedish Cancer foundation, the Association for International Cancer Research and the Novo Nordisk Foundation.

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Trends in Biochemical Sciences

VEGF-receptor signal transduction

Abstract

Section snippets

The VEGFs

Expression, signal transduction and function of VEGFR-1

Expression, signal transduction and function of VEGFR-2

Expression, signal transduction and function of VEGFR-3

Concluding remarks and future perspectives

Acknowledgements

Semin. Oncol.

Blood

Blood

J. Biol. Chem.

Biochem. Biophys. Res. Commun.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

Int. J. Biochem. Cell Biol.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

Exp. Cell Res.

Mol. Cell

J. Biol. Chem.

Cell

Trends Cardiovasc. Med.

Cell

Genomics

Blood

Semin. Cell Dev. Biol.

Blood

Cancer Cell

Hypoxia – a key regulatory factor in tumour growth

Nat. Rev. Cancer

Vascular and haematopoietic stem cells: novel targets for anti-angiogenesis therapy?

Nat. Rev. Cancer

Lymphatic endothelium: a new frontier of metastasis research

Nat. Cell Biol.

Impaired myocardial angiogenesis and ischemic cardiomyopathy in mice lacking the vascular endothelial growth factor isoforms VEGF164 and VEGF188

Nat. Med.

A highly conserved vascular permeability factor secreted by a variety of human and rodent tumor cell lines

Cancer Res.

Activation of vascular endothelial growth factor gene transcription by hypoxia-inducible factor 1

Mol. Cell. Biol.

Vascular permeability factor/vascular endothelial growth factor induces lymphangiogenesis as well as angiogenesis

J. Exp. Med.

Vascular growth factors and lymphangiogenesis

Physiol. Rev.

Homologs of vascular endothelial growth factor are encoded by the poxvirus orf virus

J. Virol.

Role of the Flt-1 receptor tyrosine kinase in regulating the assembly of vascular endothelium

Nature

Increased hemangioblast commitment, not vascular disorganization, is the primary defect in flt-1 knock-out mice

Development

A vascular endothelial growth factor antagonist is produced by the human placenta and released into the maternal circulation

Biol. Reprod.

Flt-1 lacking the tyrosine kinase domain is sufficient for normal development and angiogenesis in mice

Proc. Natl. Acad. Sci. U. S. A.

VEGF regulates haematopoietic stem cell survival by an internal autocrine loop mechanism

Nature

Placental growth factor reconstitutes hematopoiesis by recruiting VEGFR1(+) stem cells from bone-marrow microenvironment

Nat. Med.

Involvement of Flt-1 tyrosine kinase (vascular endothelial growth factor receptor-1) in pathological angiogenesis

Cancer Res.