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Vascular endothelial cells undergo morphogenesis into capillary networks in response to angiogenic factors. We show here that sphingosine-1-phosphate (SPP), a platelet-derived bioactive lipid, activates the EDG-1 and -3 subtypes of G protein–coupled receptors on endothelial cells to regulate angiogenesis. SPP induces the G_i/mitogen-activated protein kinase/cell survival pathway and the small GTPase Rho- and Rac-coupled adherens junction assembly. Both EDG-1- and EDG-3-regulated signaling pathways are required for endothelial cell morphogenesis into capillary-like networks. Indeed, SPP synergized with polypeptide angiogenic growth factors in the formation of mature neovessels in vivo. These data define SPP as a novel regulator of angiogenesis.