Sphingosine-1-phosphate receptor 1 （S1PR1）, a G protein-coupled recep （GPCR）. controls vasct stability by stabilizing vascular endothelial （VE）-cadherin junctional localization and inhibiting vascular endothelia...Sphingosine-1-phosphate receptor 1 （S1PR1）, a G protein-coupled recep （GPCR）. controls vasct 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 S1PR1 signaling to intracellular effectors remain unknown.In this study,we demonstrate that the heterotrimeric G protein subfamily member Gαs, 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 -spectific deletion of Gαs in mice causes early embryonic lethality with massive hemorrhage and a disorganized Vaseuiature.The immunostaining results revealed that Gαs deletion remarkably reduces the junctional localization of VE-cadherin, whereas the mull cell coverage of the vessels is not impaired.In addition, we found-that Gαs depletion blocks the S1PR1-activation induced VE-cadherin stabilization at junctons,supporting that Gαs acts downstream of S1PR1 signaling ThuS, our results demonstrate that Gαs is an essential mediator to relay S1PR1 signaling and maintain vascular integrity.展开更多
基金partially supported by the grants from the Ministry of Science & Technology-China (Nos.2014CB964600 and 2012CB966800)the National Science Foundation of China (Nos. 31301125 and 31071283)+2 种基金Shenzhen Peacock Plan (No. KQCX20130628112914292)Shenzhen Key Laboratory for Molecular Biology of Neural Development (No. ZDSY20120617112838879)SIAT Innovation Program for Excellent Young Researchers (No. 201404)
文摘Sphingosine-1-phosphate receptor 1 （S1PR1）, a G protein-coupled recep （GPCR）. controls vasct 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 S1PR1 signaling to intracellular effectors remain unknown.In this study,we demonstrate that the heterotrimeric G protein subfamily member Gαs, 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 -spectific deletion of Gαs in mice causes early embryonic lethality with massive hemorrhage and a disorganized Vaseuiature.The immunostaining results revealed that Gαs deletion remarkably reduces the junctional localization of VE-cadherin, whereas the mull cell coverage of the vessels is not impaired.In addition, we found-that Gαs depletion blocks the S1PR1-activation induced VE-cadherin stabilization at junctons,supporting that Gαs acts downstream of S1PR1 signaling ThuS, our results demonstrate that Gαs is an essential mediator to relay S1PR1 signaling and maintain vascular integrity.
