VEGF Family Ligand-Receptor Interactions

Vascular endothelial growth factors (VEGF) are a family of growth factors that stimulate the growth of new blood vessels. The VEGF family currently consists of five known members: PLGF, VEGFA, VEGFB, VEGFC and VEGFD. They are a part of the system that restores the oxygen supply to tissues when blood circulation is inadequate. VEGF creates new blood vessels during embryonic development, after injury, in muscle following exercise, and in new vessels (collateral circulation) to bypass blocked vessels. Thus, VEGF signaling is critical to the processes of angiogenesis and tumor growth. VEGF acts via endothelial-specific receptor tyrosine kinases, namely VEGFR1, VEGFR2 (KDR/Flk1) and VEGFR3 (FLT4). Besides the VEGFR, NRP1 is also expressed in endothelial cells and functions as an isoform-specific receptor for VEGF-A, -B, -C and PLGF. Disruption of the genes encoding either VEGF or any of their receptors results in embryonic lethality because of failure of development of blood vessels.A number of signal transduction molecules are activated in response to VEGF stimulation in primary endothelial cells including PI3K, PLCγ, and the SHC proteins. Activation of PI3K results in accumulation of PIP3, which in turn mediates membrane targeting and phosphorylation of AKT. AKT plays an essential role in the survival of endothelial cells. VEGF signals are also essential for endothelial cell migration, cell proliferation, and actin re-organization. PLCγ activated downstream of VEGFR catalyzes the hydrolysis of PIP2 to generate IP3 and DAG, which are known to stimulate the release of Ca2+ from internal stores and activate PKC, respectively. VEGF-induced Ras activation involves SHC. Ras in turn activates ERK signaling. VEGF also induces PKC-dependent, Ras-independent induction of the Raf1-MEK1/2-ERK1/2-cPLA2 pathway in endothelial cells. These mechanisms ultimately control vasopermeability and angiogenesis. Not only does VEGF play an essential role in the normal development and differentiation of the vascular system, it also plays a key role in pathologic angiogenesis such as tumor angiogenesis.