Gαs Relays Sphingosine-1-Phosphate Receptor 1 Signaling to Stabilize Vascular Endothelial-Cadherin at Endothelial Junctions to Control Mouse Embryonic Vascular Integrity

Sphingosine-1-phosphate receptor 1(S1PR1),a G protein-coupled receptor(GPCR),controls vascular stability by stabilizing vascular endothelial(VE)-cadherin junctional localization and inhibiting vascular endothelial growth factor receptor 2(VEGFR2) signaling.However,the molecular mechanisms that link S 1PR1 signaling to intracellular effectors remain unknown,In this study,we demonstrate that the heterotrimeric G protein subfamily member Gα_s,encoded by GNAS,acts as a relay mediator of S1PR1 signaling to control vascular integrity by stabilizing VE-cadherin at endothelial junctions.The endothelial cell-specific deletion of Gαs in mice causes early embryonic lethality with massive hemorrhage and a disorganized vasculature.The immunostalning results revealed that Gα_s deletion remarkably reduces the junctional localization of VE-cadherin,whereas the mural cell coverage of the vessels is not impaired.In addition,we found that Gαs depletion blocks the S1PRl-activation induced VE-cadherin stabilization at junctions,supporting that Gα_s acts downstream of S1PR1 signaling,Thus,our results demonstrate that Gα_s is an essential mediator to relay S1PR1 signaling and maintain vascular integrity.