Sequential roles of PDGF-B/TGF-β/S1P in smooth muscle infiltration into vessels. During angiogenesis, endothelial cells that are yet to form a mature vascular lumen secrete PDGF-B to recruit smooth muscle precursor cells to their immediate vicinity. Once the smooth muscle precursors are recruited, they are induced to differentiate to smooth muscle cells via activation of TGF-β pathways. As endothelial cells form a new lumen during angiogenesis, differentiated smooth muscle cells migrate along the endothelial cells to surround the vessels and establish a mature vasculature. This later process seems to be regulated via S1P. Two possible mechanisms are proposed for the action of S1P. S1P may control smooth muscle cell migration directly. Alternatively, S1P may act on other cells such as endothelial cells and indirectly regulates the migration of smooth muscle cells, either by inducing the expression of a putative chemoattractant(s) or by generating a permissive microenvironment for the migration. Work in a parallel developmental pathway in zebrafish argues for the latter model. Yellow cells, smooth muscle precursors; dark orange arrows, PDGF-B; blue cells, endothelial cells; orange cells, smooth muscle cells; gray arrows, TGF-β; white boxes, Edg-1; purple arrows, S1P; green arrows, chemoattractant(s) or permissive microenvironment.