© 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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