Signaling transduction mechanisms mediating biological actions of the vascular endothelial growth factor family

Abstract

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.

Differential Involvement of D1 and D2 Dopamine Receptors in L-DOPA-Induced Angiogenic Activity in a Rat Model of Parkinson's Disease

“…Activation of ERK1/2 also plays a central role in endothelial proliferation in different model systems (reviewed in Zachary and Gliki, 2001). To verify the involvement of ERK1/2 in L-DOPA-induced angiogenesis, 6-OHDA-lesioned rats were co-treated with L-DOPA and the MEK inhibitor, SL327 (which selectively inhibits ERK activation).…”

Increased revascularization efficacy after administration of an adenovirus encoding VEGF121

“…31 VEGF is expressed through alternative splicing giving rise to at least five isoforms coding for proteins of 206, 189, 165, 145, and 121 amino acids. 32,33 VEGF binds to two highly specific tyrosine kinase receptors, Flt-1 and KDR/Flk-1, found almost exclusively on endothelial cells. [34][35][36] Following receptor binding, endothelial cells are stimulated to proliferate and form tube-like structures, the first steps in forming new blood vessels, a process known as angiogenesis.…”

phospholipase C gamma-1is required downstream ofvascular endothelial growth factorduring arterial development

“…In particular, vascular endothelial growth factor (Vegf) is required for the development of arteries (Mukouyama et al 2002;Stalmans et al 2002) and the differentiation of arterial endothelial cells Mukouyama et al 2002) during embryonic development in both zebrafish and mouse. Despite the wealth of information concerning components of the Vegf signaling pathway in endothelial cell lines (Zachary and Gliki 2001), little is known about the downstream factors that are necessary in vivo during blood vessel formation and arterial development. In this study, we have taken advantage of transgenic zebrafish with fluorescently labeled blood vessels (Lawson and Weinstein 2002a) in conjunction with a forward genetic screen to identify a gene within the Vegf signaling pathway that is required for arterial development.…”