Blood vessels are constructed by two processes: vasculogenesis, whereby a primitive vascular network is established during embryogenesis from multipotential mesenchymal progenitors, and angiogenesis, in which preexisting vessels (both in embryo and adult) send out capillary sprouts to produce new vessels (1–3). Endothelial cells are centrally involved in each process: They migrate and proliferate and then assemble into tubes with tight cell-cell connections to contain the blood. Peri-endothelial support cells are recruited to encase the endothelial tubes, providing maintenance and modulatory functions to the vessels; such cells include pericytes for small capillaries, smooth muscle cells for larger vessels, and myocardial cells in the heart.

The establishment and remodeling of blood vessels is controlled by paracrine signals, many of which are protein ligands that bind and modulate the activity of transmembrane receptor tyrosine kinases (RTKs). This realization has emerged from the discovery and analysis of RTKs expressed on endothelial cells and of their ligands. Our basic view of RTK signaling has come from studies (performed largely in fibroblasts) of ligand-dependent autophosphorylation and activation of the branched Ras pathways. The results suggest that most RTKs are similarly coupled into the intracellular signal transduction cascade and are capable of inducing cell proliferation. However, the lessons from endothelial cells present a far more complicated picture. This complexity is highlighted by an article in this issue (4, page 55) of a ligand, called angiopoietin-2 (Ang2), that interferes with the kinase activity of an endothelial cell-selective RTK named Tie2. Remarkably, this inhibition of Tie2 kinase activity does not block endothelial cell proliferation and angiogenesis, but rather facilitates it.