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Vol. 52, Issue 4, 639-672, December 2000
Medical Research Council of Canada Multidisciplinary
Research Group on Hypertension, Clinical Research Institute of
Montreal, University of Montreal, Quebec, Canada
I. Introduction
II. Physiological Actions of Angiotensin II in Vascular
Smooth Muscle Cells
A. The Renin Angiotensin System
Production of Angiotensin II
B. Angiotensin Receptors
C. Vascular Actions of Angiotensin II
D. Angiotensin II-Dependent Signaling Pathways
E. Immediate Signaling Events Stimulated by Angiotensin II
1. Stimulation of Phospholipase C and Phosphatidylinositol
Hydrolysis.
2. Increased Intracellular Free Calcium
Concentration.
3. Activation of Protein Kinase C.
4. Stimulation of Na+/H+
Exchange.
5. Angiotensin II Increases Intracellular Free Concentrations of
Na+ and Decreases Intracellular Free Concentrations of
Mg2+.
6. Activation of Src Family Kinases.
F. Early Signaling Events Mediated by Angiotensin II
1. Activation of Tyrosine Kinases.
a. Janus family kinases.
b. Focal adhesion kinase and proline-rich tyrosine kinase
2.
c. p130Cas.
d. Phosphatidylinositol 3-kinase.
2. Mitogen-Activated Protein Kinase Pathways.
a. Upstream events.
b. Downstream events.
c. Angiotensin II and the mitogen-activated protein kinase pathway
in cardiovascular cells.
3. Activation of Phospholipase A2 and Arachidonic Acid
Metabolism.
4. Phospholipase D activation.
5. Angiotensin II Effects on Cyclic Nucleotides.
G. Long-Term Effects Mediated by Angiotensin II
1. Generation of Reactive Oxygen Species.
2. Angiotensin II-Induced Expression of Proto-Oncogenes and Growth
Factors.
H. Why the Special Role for Angiotensin II Signaling in Vascular
Smooth Muscle Cells?
II. Altered Angiotensin II Signaling in Vascular Smooth Muscle
Cells in Cardiovascular Diseases
Special Reference to Hypertension
A. Introduction
B. Vascular Changes
C. Vascular Angiotensin Receptors
D. Short-Term Signaling Events
1. Angiotensin II Stimulation of the Phospholipase
C-IP3-Diacylglycerol Pathway Is Augmented.
2. Angiotensin II-Stimulated Effects on Vascular
[Mg2+]i and
[Na+]i.
3. Vascular Eicosanoids, Angiotensin II, and
Hypertension.
4. Angiotensin II Increases Activity of Phospholipase D.
5. Cyclic Nucleotides and Angiotensin II.
E. Long-Term Signaling Events
1. Angiotensin II-Induced Generation of Reactive Oxygen
Species.
2. Angiotensin II, Tyrosine Kinases, and Hypertension.
3. Angiotensin II-Mediated Mitogen-Activated Protein Kinase
Signaling Is Increased.
4. Indirect Effects of Angiotensin II on the Vasculature.
F. Mechanisms Underlying Enhanced Angiotensin II Vascular
Responsiveness
IV. Conclusions
Acknowledgment
References
Until recently, the signaling events elicited in vascular smooth muscle cells by angiotensin II (Ang II) were considered to be rapid, short-lived, and divided into separate linear pathways, where intracellular targets of the phospholipase C-diacylglycerol-Ca2+ axis were distinct from those of the tyrosine kinase- and mitogen-activated protein kinase- dependent pathways. However, these major intracellular signaling cascades do not function independently and are actively engaged in cross-talk. Downstream signals from the Ang II-bound receptors converge to elicit complex and multiple responses. The exact adapter proteins or "go-between" molecules that link the multiple intracellular pathways await clarification. Ang II induces a multitude of actions in various tissues, and the signaling events following occupancy and activation of angiotensin receptors are tightly controlled and extremely complex. Alterations of these highly regulated signaling pathways in vascular smooth cells may be pivotal in structural and functional abnormalities that underlie vascular pathological processes in cardiovascular diseases such as hypertension, atherosclerosis, and post-interventional restenosis.
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P. Pladys, F. Sennlaub, S. Brault, D. Checchin, I. Lahaie, N. L. O. Le, K. Bibeau, G. Cambonie, D. Abran, M. Brochu, et al. Microvascular rarefaction and decreased angiogenesis in rats with fetal programming of hypertension associated with exposure to a low-protein diet in utero Am J Physiol Regulatory Integrative Comp Physiol, December 1, 2005; 289(6): R1580 - R1588. [Abstract] [Full Text] [PDF]
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E. A. Woolfolk, S. Eguchi, H. Ohtsu, H. Nakashima, H. Ueno, W. T. Gerthoffer, and E. D. Motley Angiotensin II-induced activation of p21-activated kinase 1 requires Ca2+ and protein kinase C{delta} in vascular smooth muscle cells Am J Physiol Cell Physiol, November 1, 2005; 289(5): C1286 - C1294. [Abstract] [Full Text] [PDF]
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C. De Ciuceis, F. Amiri, P. Brassard, D. H. Endemann, R. M. Touyz, and E. L. Schiffrin Reduced Vascular Remodeling, Endothelial Dysfunction, and Oxidative Stress in Resistance Arteries of Angiotensin II-Infused Macrophage Colony-Stimulating Factor-Deficient Mice: Evidence for a Role in Inflammation in Angiotensin-Induced Vascular Injury Arterioscler. Thromb. Vasc. Biol., October 1, 2005; 25(10): 2106 - 2113. [Abstract] [Full Text] [PDF]
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I. Haulica, W. Bild, and D. N Serban Review: Angiotensin Peptides and their Pleiotropic Actions Journal of Renin-Angiotensin-Aldosterone System, September 1, 2005; 6(3): 121 - 131. [Abstract] [PDF]
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H. Ohtsu, M. Mifune, G. D. Frank, S. Saito, T. Inagami, S. Kim-Mitsuyama, Y. Takuwa, T. Sasaki, J. D. Rothstein, H. Suzuki, et al. Signal-Crosstalk Between Rho/ROCK and c-Jun NH2-Terminal Kinase Mediates Migration of Vascular Smooth Muscle Cells Stimulated by Angiotensin II Arterioscler. Thromb. Vasc. Biol., September 1, 2005; 25(9): 1831 - 1836. [Abstract] [Full Text] [PDF]
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P. Brassard, F. Amiri, and E. L. Schiffrin Combined Angiotensin II Type 1 and Type 2 Receptor Blockade on Vascular Remodeling and Matrix Metalloproteinases in Resistance Arteries Hypertension, September 1, 2005; 46(3): 598 - 606. [Abstract] [Full Text] [PDF]
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J. Yu, K. Mizumoto, Y. Tokinaga, K. Ogawa, and Y. Hatano The Inhibitory Effects of Sevoflurane on Angiotensin II- Induced, p44/42 Mitogen-Activated Protein Kinase-Mediated Contraction of Rat Aortic Smooth Muscle Anesth. Analg., August 1, 2005; 101(2): 315 - 321. [Abstract] [Full Text] [PDF]
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M. Mifune, H. Ohtsu, H. Suzuki, H. Nakashima, E. Brailoiu, N. J. Dun, G. D. Frank, T. Inagami, S. Higashiyama, W. G. Thomas, et al. G Protein Coupling and Second Messenger Generation Are Indispensable for Metalloprotease-dependent, Heparin-binding Epidermal Growth Factor Shedding through Angiotensin II Type-1 Receptor J. Biol. Chem., July 15, 2005; 280(28): 26592 - 26599. [Abstract] [Full Text] [PDF]
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U. G. B. Haider, T. U. Roos, M. I. Kontaridis, B. G. Neel, D. Sorescu, K. K. Griendling, A. M. Vollmar, and V. M. Dirsch Resveratrol Inhibits Angiotensin II- and Epidermal Growth Factor-Mediated Akt Activation: Role of Gab1 and Shp2 Mol. Pharmacol., July 1, 2005; 68(1): 41 - 48. [Abstract] [Full Text] [PDF]
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R. M Touyz Intracellular mechanisms involved in vascular remodelling of resistance arteries in hypertension: role of angiotensin II Exp Physiol, July 1, 2005; 90(4): 449 - 455. [Abstract] [Full Text] [PDF]
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B. Gurzu, M. Costuleanu, S. M. Slatineanu, A. Ciobanu, and G. Petrescu Are Multiple Angiotensin Receptor Types Involved in Angiotensin (1-7) Actions on Isolated Rat Portal Vein? Journal of Renin-Angiotensin-Aldosterone System, June 1, 2005; 6(2): 90 - 95. [Abstract] [PDF]
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S. Wesseling, D. A. Ishola Jr., J. A. Joles, H. A. Bluyssen, H. A. Koomans, and B. Braam Resistance to oxidative stress by chronic infusion of angiotensin II in mouse kidney is not mediated by the AT2 receptor Am J Physiol Renal Physiol, June 1, 2005; 288(6): F1191 - F1200. [Abstract] [Full Text] [PDF]
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F. A. Yaghini, C. Zhang, J.-H. Parmentier, A. M. Estes, N. Jafari, S. A. Schaefer, and K. U. Malik Contribution of Arachidonic Acid Metabolites Derived Via Cytochrome P4504A to Angiotensin II-Induced Neointimal Growth Hypertension, June 1, 2005; 45(6): 1182 - 1187. [Abstract] [Full Text] [PDF]
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 C. Vecchione, E. Patrucco, G. Marino, L. Barberis, R. Poulet, A. Aretini, A. Maffei, M. T. Gentile, M. Storto, O. Azzolino, et al. Protection from angiotensin II-mediated vasculotoxic and hypertensive response in mice lacking PI3K{gamma} J. Exp. Med., April 18, 2005; 201(8): 1217 - 1228. [Abstract] [Full Text] [PDF]
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D. L. Hunton, W. G. Barnes, J. Kim, X.-R. Ren, J. D. Violin, E. Reiter, G. Milligan, D. D. Patel, and R. J. Lefkowitz {beta}-Arrestin 2-Dependent Angiotensin II Type 1A Receptor-Mediated Pathway of Chemotaxis Mol. Pharmacol., April 1, 2005; 67(4): 1229 - 1236. [Abstract] [Full Text] [PDF]
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Q. Che and P. K. Carmines Src family kinase involvement in rat preglomerular microvascular contractile and [Ca2+]i responses to ANG II Am J Physiol Renal Physiol, April 1, 2005; 288(4): F658 - F664. [Abstract] [Full Text] [PDF]
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W. G. Barnes, E. Reiter, J. D. Violin, X.-R. Ren, G. Milligan, and R. J. Lefkowitz {beta}-Arrestin 1 and G{alpha}q/11 Coordinately Activate RhoA and Stress Fiber Formation following Receptor Stimulation J. Biol. Chem., March 4, 2005; 280(9): 8041 - 8050. [Abstract] [Full Text] [PDF]
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 A. Modesti, I. Bertolozzi, T. Gamberi, M. Marchetta, C. Lumachi, M. Coppo, F. Moroni, T. Toscano, G. Lucchese, G. F. Gensini, et al. Hyperglycemia Activates JAK2 Signaling Pathway in Human Failing Myocytes via Angiotensin II-Mediated Oxidative Stress Diabetes, February 1, 2005; 54(2): 394 - 401. [Abstract] [Full Text] [PDF]
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M. Otis, S. Campbell, M. D. Payet, and N. Gallo-Payet Angiotensin II Stimulates Protein Synthesis and Inhibits Proliferation in Primary Cultures of Rat Adrenal Glomerulosa Cells Endocrinology, February 1, 2005; 146(2): 633 - 642. [Abstract] [Full Text] [PDF]
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K.H.S. Arun, C.L. Kaul, and P. Ramarao AT1 receptors and L-type calcium channels: functional coupling in supersensitivity to angiotensin II in diabetic rats Cardiovasc Res, February 1, 2005; 65(2): 374 - 386. [Abstract] [Full Text] [PDF]
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C. S. Wilcox and D. Gutterman Focus on oxidative stress in the cardiovascular and renal systems Am J Physiol Heart Circ Physiol, January 1, 2005; 288(1): H3 - H6. [Full Text] [PDF]
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R. D. Roghair, F. S. Lamb, F. J. Miller Jr., T. D. Scholz, and J. L. Segar Early gestation dexamethasone programs enhanced postnatal ovine coronary artery vascular reactivity Am J Physiol Regulatory Integrative Comp Physiol, January 1, 2005; 288(1): R46 - R53. [Abstract] [Full Text] [PDF]
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R. P. Brandes and J. Kreuzer Vascular NADPH oxidases: molecular mechanisms of activation Cardiovasc Res, January 1, 2005; 65(1): 16 - 27. [Abstract] [Full Text] [PDF]
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 C. Zeng, H. Sanada, H. Watanabe, G. M. Eisner, R. A. Felder, and P. A. Jose Functional genomics of the dopaminergic system in hypertension Physiol Genomics, November 17, 2004; 19(3): 233 - 246. [Abstract] [Full Text] [PDF]
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 P. Li, S. Oparil, W. Feng, and Y.-F. Chen Hypoxia-responsive growth factors upregulate periostin and osteopontin expression via distinct signaling pathways in rat pulmonary arterial smooth muscle cells J Appl Physiol, October 1, 2004; 97(4): 1550 - 1558. [Abstract] [Full Text] [PDF]
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C. M. Filipeanu, F. Zhou, W. C. Claycomb, and G. Wu Regulation of the Cell Surface Expression and Function of Angiotensin II Type 1 Receptor by Rab1-mediated Endoplasmic Reticulum-to-Golgi Transport in Cardiac Myocytes J. Biol. Chem., September 24, 2004; 279(39): 41077 - 41084. [Abstract] [Full Text] [PDF]
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 R. M. Melnychuk, D. N. Streblow, P. P. Smith, A. J. Hirsch, D. Pancheva, and J. A. Nelson Human Cytomegalovirus-Encoded G Protein-Coupled Receptor US28 Mediates Smooth Muscle Cell Migration through G{alpha}12 J. Virol., August 1, 2004; 78(15): 8382 - 8391. [Abstract] [Full Text] [PDF]
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E. L. Schiffrin and R. M. Touyz From bedside to bench to bedside: role of renin-angiotensin-aldosterone system in remodeling of resistance arteries in hypertension Am J Physiol Heart Circ Physiol, August 1, 2004; 287(2): H435 - H446. [Full Text] [PDF]
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Y. Shimoni and X.-F. Liu Gender differences in ANG II levels and action on multiple K+ current modulation pathways in diabetic rats Am J Physiol Heart Circ Physiol, July 1, 2004; 287(1): H311 - H319. [Abstract] [Full Text] [PDF]
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 G. Wang, J. Anrather, J. Huang, R. C. Speth, V. M. Pickel, and C. Iadecola NADPH Oxidase Contributes to Angiotensin II Signaling in the Nucleus Tractus Solitarius J. Neurosci., June 16, 2004; 24(24): 5516 - 5524. [Abstract] [Full Text] [PDF]
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 G. H. Goossens, E. E. Blaak, W. H. M. Saris, and M. A. van Baak Angiotensin II-Induced Effects on Adipose and Skeletal Muscle Tissue Blood Flow and Lipolysis in Normal-Weight and Obese Subjects J. Clin. Endocrinol. Metab., June 1, 2004; 89(6): 2690 - 2696. [Abstract] [Full Text] [PDF]
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 V. Esteban, O. Lorenzo, M. Ruperez, Y. Suzuki, S. Mezzano, J. Blanco, M. Kretzler, T. Sugaya, J. Egido, and M. Ruiz-Ortega Angiotensin II, via AT1 and AT2 Receptors and NF-{kappa}B Pathway, Regulates the Inflammatory Response in Unilateral Ureteral Obstruction J. Am. Soc. Nephrol., June 1, 2004; 15(6): 1514 - 1529. [Abstract] [Full Text] [PDF]
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P. Zahradka, B. Litchie, B. Storie, and G. Helwer Transactivation of the Insulin-Like Growth Factor-I Receptor by Angiotensin II Mediates Downstream Signaling from the Angiotensin II Type 1 Receptor to Phosphatidylinositol 3-Kinase Endocrinology, June 1, 2004; 145(6): 2978 - 2987. [Abstract] [Full Text] [PDF]
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F. Andreozzi, E. Laratta, A. Sciacqua, F. Perticone, and G. Sesti Angiotensin II Impairs the Insulin Signaling Pathway Promoting Production of Nitric Oxide by Inducing Phosphorylation of Insulin Receptor Substrate-1 on Ser312 and Ser616 in Human Umbilical Vein Endothelial Cells Circ. Res., May 14, 2004; 94(9): 1211 - 1218. [Abstract] [Full Text] [PDF]
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M. E. Mabrouk, Q. N. Diep, K. Benkirane, R. M. Touyz, and E. L. Schiffrin SAM68: a downstream target of angiotensin II signaling in vascular smooth muscle cells in genetic hypertension Am J Physiol Heart Circ Physiol, May 1, 2004; 286(5): H1954 - H1962. [Abstract] [Full Text] [PDF]
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 M. B. Hussain, S. Singhal, H. S. Markus, and D. R.J. Singer Abnormal Vasoconstrictor Responses to Angiotensin II and Noradrenaline in Isolated Small Arteries From Patients With Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy (CADASIL) Stroke, April 1, 2004; 35(4): 853 - 858. [Abstract] [Full Text] [PDF]
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