title: Gαs Relays Sphingosine-1-Phosphate Receptor 1 Signaling to Stabilize Vascular Endothelial-Cadherin at Endothelial Junctions to Control Mouse Embryonic Vascular Integrity.
abstract: 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 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-specific deletion of Gαs in mice causes early embryonic lethality with massive hemorrhage and a disorganized vasculature. The immunostaining results revealed that Gαs 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 S1PR1-activation induced VE-cadherin stabilization at junctions, 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.
authors.affiliation: West China Developmental and Stem Cell Institute, West China Second Hospital, Sichuan University, Chengdu 610041, China; State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu 610041, China; Shenzhen Key Laboratory for Molecular Biology of Neural Development, Laboratory of Developmental and Regenerative Biology, Institute of Biomedicine and Biotechnology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China.
authors.forename: Ximing
authors.initials: X
authors.lastname: Shao
authors.affiliation: West China Developmental and Stem Cell Institute, West China Second Hospital, Sichuan University, Chengdu 610041, China; State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu 610041, China; Shenzhen Key Laboratory for Molecular Biology of Neural Development, Laboratory of Developmental and Regenerative Biology, Institute of Biomedicine and Biotechnology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China.
authors.forename: Ke
authors.initials: K
authors.lastname: Liu
authors.affiliation: West China Developmental and Stem Cell Institute, West China Second Hospital, Sichuan University, Chengdu 610041, China; State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu 610041, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Fan
authors.affiliation: Shenzhen Key Laboratory for Molecular Biology of Neural Development, Laboratory of Developmental and Regenerative Biology, Institute of Biomedicine and Biotechnology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China.
authors.forename: Zhihao
authors.initials: Z
authors.lastname: Ding
authors.affiliation: National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Min
authors.initials: M
authors.lastname: Chen
authors.affiliation: SARITEX Center for Stem Cell Engineering Translational Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200123, China.
authors.forename: Minyan
authors.initials: M
authors.lastname: Zhu
authors.affiliation: National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Lee S
authors.initials: LS
authors.lastname: Weinstein
authors.affiliation: Shenzhen Key Laboratory for Molecular Biology of Neural Development, Laboratory of Developmental and Regenerative Biology, Institute of Biomedicine and Biotechnology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China. Electronic address: hc.li@siat.ac.cn.
authors.forename: Hongchang
authors.initials: H
authors.lastname: Li
authors.affiliation: West China Developmental and Stem Cell Institute, West China Second Hospital, Sichuan University, Chengdu 610041, China; State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu 610041, China; SARITEX Center for Stem Cell Engineering Translational Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200123, China; Nerdbio Inc., SIP Biobay, Suzhou 215213, China. Electronic address: huashunli@tongji.edu.cn.
authors.forename: Huashun
authors.initials: H
authors.lastname: Li
mesh_terms: D022005:Adherens Junctions / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism*; D001808:Blood Vessels / Q000033:anatomy & histology / Q000196:embryology / Q000378:metabolism*; D015820:Cadherins / Q000235:genetics / Q000378:metabolism*; D002864:Chromogranins; D042783:Endothelial Cells / Q000378:metabolism*; D005260:Female; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D049349:Receptors, Lysosphingolipid / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D000081025:Sphingosine-1-Phosphate Receptors; D000099152:Cadherin 5
chemical_list: D015703:Antigens, CD; D015820:Cadherins; D002864:Chromogranins; D019205:GTP-Binding Protein alpha Subunits, Gs; D049349:Receptors, Lysosphingolipid; D000081025:Sphingosine-1-Phosphate Receptors; D000099152:Cadherin 5; C556330:S1pr1 protein, mouse; C498642:Gnas protein, mouse
keywords: Gα(s); S1PR1 signaling; VE-cadherin; adherens junctions; vascular integrity