Vascular development: genetic mechanisms and links to vascular disease

Vertebrate development depends on the formation of intricate vascular networks at numerous sites and in precise patterns; these vascular networks supply oxygen and nutrients to the rapidly expanding tissues of the embryo. Embryonic blood vessels are composed of endothelial cells and pericytes that organize and expand into highly branched conduits. Proper development of the vasculature requires heterogeneity in the response of endothelial cells to angiogenic cues provided by other tissues and organs. The pathogenesis of vascular diseases results from genetic mutations in pathways that provide these cues and in signals that coordinate endothelial heterogeneity during blood vessel formation. Here we provide a brief overview of different aspects of blood vessel formation and then discuss three essential signaling pathways that help establish vessel networks and maintain endothelial phenotypic heterogeneity during vascular development: the vascular endothelial growth factor (VEGF), bone morphogenetic protein (BMP), and the Notch/Delta/Jagged pathways. The VEGF pathway is critical for the initiation and spatial coordination of angiogenic sprouting and endothelial proliferation, BMP signaling appears to act in a context-dependent manner to promote angiogenic expansion and remodeling, and the Notch pathway is a critical integrator of endothelial cell phenotypes and heterogeneity. We also discuss human genetic mutations that affect these pathways and the resulting pathological conditions.