ADAM-Mediated Shedding, A New Flavor in Angiogenesis Regulation

Vascular endothelial growth factor (VEGF) is a key regulator of angiogenesis (ie, blood vessel formation). VEGF acts by binding to the VEGF receptor 2 (VEGFR2) tyrosine kinase, expressed on endothelial cells. In healthy individuals, the vasculature is quiescent; invasion of vascular sprouts into the surrounding tissue during angiogenesis is tightly regulated by the Notch family of ligands and receptors. VEGF is also a critical regulator of vascular permeability, which involves disruption of endothelial adherens junctions through disengagement of vascular endothelial (VE) cadherin.1See accompanying article on page 2188 Both Notch family receptors and VE-cadherin belong to a wide range of molecules known to be posttranslationally modified by shedding through “a disintegrin and metalloproteinase” (ADAM) proteins, which form the ADAM family of sheddases. The ADAMs are cell surface–localized transmembrane enzymes that act to release ectodomains of membrane proteins, leading to removal of membrane …