Mechanisms Underlying Context-Dependent VEGF Signaling For Distinct Biological Responses

Vascular endothelial growth factor (VEGF) is a signal protein produced by cells that stimulates vasculogenesis and angiogenesis. It is part of the system that restores the oxygen supply to tissues when blood circulation is inadequate. VEGF signaling is essential for specification, morphogenesis, differentiation, and homeostasis of vessels during development and in the adult. Furthermore, this signaling pathway is an integral component of pathological angiogenesis during tumor expansion. In fact, decreased levels of VEGF result in suppression of vascular expansion, tumor growth, and metastasis, making anti-angiogenesis an appealing cancer therapy. The VEGFA gene produces diverse proteins. Both decreases and increases in VEGF levels produce significant pathological insults to the vasculature that affect the entire organism. The regulation of VEGF synthesis, secretion, and availability modulates the angiogenic response. VEGF signaling can be induced by two receptor tyrosine kinases, VEGFR1 (flt-1 or FLT-1) and VEGFR2 (flk-1 or KDR). Clinically, the most successful has been the VEGF-neutralizing antibody Bevacizumab/Avastin, which was approved by the United States Food and Drug Administration for clinical use early in 2004. Other strategies to target the VEGF pathway include soluble VEGFRs (Traps), and receptor tyrosine-kinase inhibitors (RTKI) that target VEGFR2, as well as neutralizing aptomers. Intracrine VEGF is essential for survival pathways that are not entirely redundant, as exogenous VEGF cannot rescue defects in cell survival in the absence of intracellular VEGF. Defining the distinct signaling responses initiated by soluble, bound, and intracrine VEGF remains a challenge and is the focus of ongoing research.