a | Sphingosine-1-phosphate receptor 1 (S1PR1) is expressed in vascular endothelial cells and colocalizes with vascular endothelial cadherin in regions of normal blood flow, but is internalized in regions with turbulent blood flow (not shown). b | Engagement of vascular endothelial growth factor (VEGF) signalling in the growing vascular front induces the formation of sprouts consisting of tip cells that extend out from the blood vessel and stalk cells. The sprouting vascular front, the tip and stalk cell region express very low levels of S1PR1 (REF. 88); alternatively, S1PR1 is expressed on tip cells but they are not exposed to S1P present in the bloodstream86. c | After its fusion into a primary vascular loop, which is a key step in the initiation of blood flow, S1P activates S1PR1. Activation of S1PR1 enhances the formation of adherens junctions, inhibits VEGF signalling, suppresses sprouting and stabilizes new vascular connections. VEGFR, VEGF receptor.