© 2001 by European Society of Cardiology
Copyright © 2001, European Society of Cardiology
Signaling transduction mechanisms mediating biological actions of the vascular endothelial growth factor family
Centre for Cardiovascular Biology and Medicine, Department of Medicine, University College London, 5 University Street, London WC1E 6JJ, UK
* Corresponding author. Tel.: +44-20-7679-6620; fax: +44-20-7679-6212 i.zachary{at}ucl.ac.uk
The central role of vascular endothelial growth factor (VEGF) in angiogenesis in health and disease makes it attractive both as a therapeutic target for anti-angiogenic drugs and as a pro-angiogenic cytokine for the treatment of ischaemic heart disease. While VEGF binds to two receptor protein tyrosine kinases, VEGFR1 (Flt-1) and VEGFR2 (KDR), most biological functions of VEGF are mediated via VEGFR2, and the role of VEGFR1 is currently unknown. Neuropilin-1, a non-tyrosine kinase transmembrane molecule, may function as a co-receptor for VEGFR2. Considerable progress has recently been made towards delineating the signal transduction pathways distal to activation of VEGFR2. Activation of the mitogen-activated protein kinase, protein kinase C and Akt pathways are all strongly implicated in mediating diverse cellular biological functions of VEGF, including cell survival, proliferation, the generation of nitric oxide and prostacyclin and angiogenesis. Upregulation of metalloproteinases, activation of focal adhesion kinase and interactions between VEGF receptors and integrins are strongly implicated in VEGF-induced endothelial cell migration. Recent findings suggest important roles for the vasodilators nitric oxide and prostacyclin, in linking post-receptor signaling networks to downstream biological effects and in mediating some in vivo endothelial functions of VEGF.
KEYWORDS bFGF, basic fibroblast growth factor (FGF-2); eNOS, endothelial constitutive nitric oxide synthase; ERK, extracellular signal-regulated kinase; FAK, focal adhesion kinase; HUVEC, human umbilical vein endothelial cell; PGI2, prostacyclin; PKC, protein kinase C; VEGF, vascular endothelial growth factor A; VSMC, vascular smooth muscle cell; vWF, von Willebrand factor
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 N. D. Lawson, J. W. Mugford, B. A. Diamond, and B. M. Weinstein phospholipase C gamma-1 is required downstream of vascular endothelial growth factor during arterial development Genes & Dev., June 1, 2003; 17(11): 1346 - 1351. [Abstract] [Full Text] [PDF]
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S. Nakao, T. Kuwano, T. Ishibashi, M. Kuwano, and M. Ono Synergistic Effect of TNF-{alpha} in Soluble VCAM-1-Induced Angiogenesis Through {alpha}4 Integrins J. Immunol., June 1, 2003; 170(11): 5704 - 5711. [Abstract] [Full Text] [PDF]
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V. Louzier, B. Raffestin, A. Leroux, D. Branellec, J. M. Caillaud, M. Levame, S. Eddahibi, and S. Adnot Role of VEGF-B in the lung during development of chronic hypoxic pulmonary hypertension Am J Physiol Lung Cell Mol Physiol, June 1, 2003; 284(6): L926 - L937. [Abstract] [Full Text] [PDF]
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M. Duval, S. Bedard-Goulet, C. Delisle, and J.-P. Gratton Vascular Endothelial Growth Factor-dependent Down-regulation of Flk-1/KDR Involves Cbl-mediated Ubiquitination: CONSEQUENCES ON NITRIC OXIDE PRODUCTION FROM ENDOTHELIAL CELLS J. Biol. Chem., May 23, 2003; 278(22): 20091 - 20097. [Abstract] [Full Text] [PDF]
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E. N. Johnson, Y. M. Lee, T. L. Sander, E. Rabkin, F. J. Schoen, S. Kaushal, and J. Bischoff NFATc1 Mediates Vascular Endothelial Growth Factor-induced Proliferation of Human Pulmonary Valve Endothelial Cells J. Biol. Chem., January 10, 2003; 278(3): 1686 - 1692. [Abstract] [Full Text] [PDF]
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 K. D. Miller, C. J. Sweeney, and G. W. Sledge The Snark is a Boojum: the continuing problem of drug resistance in the antiangiogenic era Ann. Onc., January 1, 2003; 14(1): 20 - 28. [Abstract] [Full Text] [PDF]
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 H. Y. Shin, M. L. Smith, K. J. Toy, P. M. Williams, R. Bizios, and M. E. Gerritsen VEGF-C mediates cyclic pressure-induced endothelial cell proliferation Physiol Genomics, December 3, 2002; 11(3): 245 - 251. [Abstract] [Full Text] [PDF]
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 T. M. Hazzard, F. Xu, and R. L. Stouffer Injection of Soluble Vascular Endothelial Growth Factor Receptor 1 into the Preovulatory Follicle Disrupts Ovulation and Subsequent Luteal Function in Rhesus Monkeys Biol Reprod, October 1, 2002; 67(4): 1305 - 1312. [Abstract] [Full Text] [PDF]
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J. C Wanstall, A. Gambino, T. K Jeffery, M. M Cahill, D. Bellomo, N. K Hayward, and G. F Kay Vascular endothelial growth factor-B-deficient mice show impaired development of hypoxic pulmonary hypertension Cardiovasc Res, August 1, 2002; 55(2): 361 - 368. [Abstract] [Full Text] [PDF]
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B. Li, A. K. Ogasawara, R. Yang, W. Wei, G.-W. He, T. F. Zioncheck, S. Bunting, A. M. de Vos, and H. Jin KDR (VEGF Receptor 2) Is the Major Mediator for the Hypotensive Effect of VEGF Hypertension, June 1, 2002; 39(6): 1095 - 1100. [Abstract] [Full Text] [PDF]
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L. Bogin and H. Degani Hormonal Regulation of VEGF in Orthotopic MCF7 Human Breast Cancer Cancer Res., April 1, 2002; 62(7): 1948 - 1951. [Abstract] [Full Text] [PDF]
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L. Vincent, C. Soria, F. Mirshahi, P. Opolon, Z. Mishal, J.-P. Vannier, J. Soria, and L. Hong Cerivastatin, an Inhibitor of 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase, Inhibits Endothelial Cell Proliferation Induced by Angiogenic Factors In Vitro and Angiogenesis in In Vivo Models Arterioscler Thromb Vasc Biol, April 1, 2002; 22(4): 623 - 629. [Abstract] [Full Text] [PDF]
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R. Yang, A. K. Ogasawara, T. F. Zioncheck, Z. Ren, G.-W. He, G. G. DeGuzman, N. Pelletier, B.-Q. Shen, S. Bunting, and H. Jin Exaggerated Hypotensive Effect of Vascular Endothelial Growth Factor in Spontaneously Hypertensive Rats Hypertension, March 1, 2002; 39(3): 815 - 820. [Abstract] [Full Text] [PDF]
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D. Thuringer, L. Maulon, and C. Frelin Rapid Transactivation of the Vascular Endothelial Growth Factor Receptor KDR/Flk-1 by the Bradykinin B2 Receptor Contributes to Endothelial Nitric-oxide Synthase Activation in Cardiac Capillary Endothelial Cells J. Biol. Chem., January 11, 2002; 277(3): 2028 - 2032. [Abstract] [Full Text] [PDF]
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L. Vincent, C. Soria, F. Mirshahi, P. Opolon, Z. Mishal, J.-P. Vannier, J. Soria, and L. Hong Cerivastatin, an Inhibitor of 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase, Inhibits Endothelial Cell Proliferation Induced by Angiogenic Factors In Vitro and Angiogenesis in In Vivo Models Arterioscler Thromb Vasc Biol, April 1, 2002; 22(4): 623 - 629. [Abstract] [Full Text] [PDF]
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