Endothelial Signal Integration in Vascular Assembly

Regulated assembly of a highly specialized interconnecting network of vascular endothelial and supportive cells is fundamental to embryonic development and organogenesis, as well as to postnatal tissue repair in metazoans. This review advances an “endotheliocentric” model that defines tasks required of endothelial cells and describes molecular controls that regulate steps in activation, assembly, and maturation of new vessels. In addition to the classical assembly mechanisms—angiogenesis and vasculogenesis—endothelial cells are also recruited into vascular structures from the circulatory system in adult animals and from resident mesenchymally derived progenitors during organogenesis of kidney and other organs. Paracrine signaling cascades regulated by hypoxia initiate a sequentially coordinated series of endothelial responses, including matrix degradation, migration, proliferation, and morphogenetic remodeling. Surface receptors on committed endothelial lineage progenitors transduce cues from extracellular-matrix–associated proteins and cell-cell contact to direct migration, matrix attachment, proliferation, targeting and cell-cell assembly, and vessel maturation. Through their capacity to spatially segregate and temporally integrate a diverse range of extracellular signals, endothelial cells determine their migratory paths, cellular partners, and life-or-death responses to local cues.