Endothelial cell activation

The initiation of the angiogenic cascade from a pre-existent vascular network requires the selective departure of individual endothelial cells from differentiated capillaries. The process entails the activation of specific signaling pathways that enable endothelial cells to exit their vessel of origin, invade the underlying stroma and initiate a new vascular sprout. Two major signaling pathways: VEGF and Notch, coordinate this process to select a subset of leading endothelial cells, referred to as tip cells. These cells display long filopodia and are highly migratory, but remain linked to their followers, the stalk cells. The stalk cells constitute the body of the sprout and proliferate in response to VEGF increasing the length of the incipient capillary. It is the coordination of Notch and VEGF signaling that regulates the extent to which cells become leaders (tip cells) and which become followers (stalk cells). Activation of Notch represses the tip cell in favor of the stalk cell phenotype, in part, by regulating the levels of VEGFR2. The resolution of the endothelial activation phase requires synthesis and organization of the basement membrane and the recruitment of pericytes and smooth muscle cells. This chapter focuses on the molecular regulation of these signaling pathways, and it contrasts our current understanding of endothelial cell activation in development and in disease.