Flow-Regulated Endothelial S1P Receptor-1 Signaling Sustains Vascular Development

During angiogenesis, nascent vascular sprouts fuse to form vascular networks, enabling efficient circulation. Mechanisms that stabilize the vascular plexus are not well understood. Sphingosine 1-phosphate (S1P) is a blood-borne lipid mediator implicated in the regulation of vascular and immune systems. Here we describe a mechanism by which the G protein-coupled S1P receptor-1 (S1P1) stabilizes the primary vascular network. A gradient of S1P1 expression from the mature regions of the vascular network to the growing vascular front was observed. In the absence of endothelial S1P1, adherens junctions are destabilized, barrier function is breached, and flow is perturbed, resulting in abnormal vascular hypersprouting. Interestingly, S1P1 responds to S1P as well as laminar shear stress to transduce flow-mediated signaling in endothelial cells both in vitro and in vivo. These data demonstrate that blood flow and circulating S1P activate endothelial S1P1 to stabilize blood vessels in development and homeostasis. [Display omitted] ► S1P1 is expressed in nascent vascular networks and suppresses hypersprouting ► Endothelial S1P1 promotes barrier function and flow in vascular networks ► Flow-mediated signaling and morphological changes require S1P1 ► Flow activates S1P1 receptor in a ligand-independent manner Jung et al. find that sphingosine 1-phosphate (S1P) receptor-1 (S1P1) suppresses hypersprouting, promotes perfusion, and maintains the barrier function of newly formed vascular networks. Their work also suggests that these functions in endothelial cells reflect parallel S1P1 responses to both S1P and the shear stress of blood flow.