VEGF Signaling in Health and Disease

Vascular Endothelial Growth Factor (VEGF), also known as vascular permeability factor, is a homodimeric 46kDa protein that signals through two main tyrosine kinase receptors, VEGFR1 (flt) and VEGFR2 (flk, KDR). In addition to these receptors, the non‐tyrosine kinase receptors: Neuropilin1 and Neuropilin2 can bind to VEGF and contribute to signaling. Activation downstream VEGF receptors have been recognized to initiate a series of events resulting in the morphogenesis of blood vessels. However, amongst all these receptors, VEGFR2 is known to be the major mediator of VEGF‐responses associated with angiogenesis. In fact, pharmacological blockade of either the VEGF or VEGFR2 results in the suppression of angiogenesis, as shown in several pathological models. These findings have resulted in the generation of antibodies and small molecule inhibitors. Many of these molecules are currently in the clinic to suppress the angiogenic cascade in cancer, vascular retinopathies and other afflictions. Interestingly, the interventions have worked well in some settings, but are not as effective in other situations. The basis for this disconnect is unclear at this point. Our laboratory has recently uncovered a novel mean for VEGFR2 activation that does require ligand and is also independent of the kinase activity of the receptor. This ligand‐independent, kinase‐independent mode of VEGR2 activation results in downstream signaling but is not affected by current modes of pharmacological blockade of the pathway. In this symposia, we will present our findings, disclose the pathway and discuss its potential impact to several pathological conditions.