VEGF Signaling

The vascular endothelial growth factor family of growth factors (VEGF) play a fundamental role in the growth and differentiation of vascular as well as lymphatic endothelial cells. In addition, VEGF is also a significant mediator of hypoxia-induced angiogenesis in pathological situations like diabetic retinopathy, tumor angiogenesis and coronary artery disease. The hypoxia inducible factor, (HIF-1) and mRNA binding protein HuR play a significant role in inducing transcription of the VEGF gene under hypoxic conditions. The angiogenic effects of VEGF are mediated via the vascular endothelium via receptor tyrosine kinases (VEGFR) that become phosphorylated upon activation.VEGF is a survival factor for endothelial cells. The anti-apoptotic activity of VEGF is mediated by the phosphatidylinositol (PI)-3 kinase-AKT pathway. AKT can counteract apoptotic signaling by phosphorylating and inactivating pro-apoptotic proteins like BAD, which results in the activation of anti-apoptotic proteins like BCL-2 in endothelial cells. AKT has also been reported to directly phosphorylate and activate endothelial nitric oxide synthase (eNOS) in a Ca2+ independent manner resulting in the production of NO in response to VEGF stimulation. The PLC-γ-PKC pathway has also been implicated in regulating the action of eNOS. VEGF induces the phosphorylation and activation of PLC-γ leading to the generation of diacylglycerols (DAG) and inositol 1, 4, 5-trisphosphate (IP3).The increase in intracellular Ca2+ due to IP3 activates eNOS, whereas diacyl-glycerol activates certain PKC isoforms. PKC in turn regulates the activity of eNOS and hence NO production. Nitric oxide plays an important role in cardiovascular homesotasis by regulating systemic blood pressure, vascular remodeling and angiogenesis.VEGF promotes endothelial cell migration by activating the Rho-dependent kinase (ROCK), which in turn phosphorylates Focal adhesion kinase (FAK) on Ser732. Proline-rich tyrosine kinase-2 (PYK2) is also activated in response to VEGF and triggers the phosphorylation of Tyr407 within FAK, an event necessary for cell migration. Phosphorylation of FAK by ROCK is a prerequisite for phosphorylation of FAK by PYK2. In addition to endothelial cell survival and migration, VEGF also promotes proliferation of endothelial cells. This is facilitated by the activation of the mitogen activated protein kinase (MAPK) pathway.This pathway highlights the important molecular events involved in VEGF signaling.