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

The central role of vascular endothelial growth factor (VEGF) in angiogenes is in health and disease makes it attractive both as a therapeutic target f or anti-angiogenic drugs and as a pro-angiogenic cytokine for the treatment of ischaemic heart disease. While VEGF binds to two receptor protein tyros ine 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 tow ards delineating the signal transduction pathways distal to activation of V EGFR2. 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-induc ed endothelial cell migration. Recent findings suggest important roles for the vasodilators nitric oxide and prostacyclin, in linking post-receptor si gnaling networks to downstream biological effects and in mediating some in vivo endothelial functions of VEGF. (C) 2001 Elsevier Science B.V. All righ ts reserved.