VEGF receptor signalling ? in control of vascular function

Abstract

Three vascular endothelial growth-factor receptors (VEGFRs) regulate vascular-endothelial, haematopoietic and lymphatic-endothelial cell function during development and in the adult. Many of these processes require balanced VEGFR signalling, which involves more than one of the VEGFRs. VEGFR1 signalling seems to be dispensable for endothelial-cell function, but it is essential for the migration of haematopoietic cells. A soluble splice variant of VEGFR1, which lacks the intracellular domain, might function as a VEGF 'trap', and is implicated in preeclampsia during pregnancy. VEGFR1 signal transduction might positively or negatively regulate VEGFR2 activity. VEGFR2 is absolutely required for endothelial-cell development and survival of blood vessels. Tyrosine phosphorylation sites in VEGFR2 regulate kinase activity and binding of phospholipase C-γ, and the adaptor molecules TSAd, Shb and Sck. VEGFR2-blocking therapies are in use or are being tested for the treatment of human malignancies. VEGFR3 is required for cardiovascular development and lymphangiogenesis. Certain VEGF family members might induce formation of heterodimers, which involves VEGFR2 and VEGFR3, thereby regulating the phosphorylation of VEGFR3 and consequent signal transduction. Co-receptors (VEGF-binding molecules that might lack intrinsic catalytic function) such as heparan-sulphate proteoglycans and neuropilins are engaged in the VEGFR signalling complex in a manner that is guided by the VEGF isoform. Co-receptors modulate the duration and quality of VEGFR signalling by the formation of VEGF gradients and by stabilizing the signalling complex. Cell?cell and cell?matrix adhesion molecules that are regulated, for example, by blood flow, affect VEGFR signalling by allowing receptor activation in the absence of VEGF. The signal from an activated VEGFR is influenced by several factors (the particular VEGF isoform, the possibility of homodimerization or heterodimerization with other VEGFRs, co-receptors or adhesion molecules) in the local milieu.