Gαs Relays Sphingosine-1-Phosphate Receptor 1 Signaling to Stabilize Vascular Endothelial-Cadherin at Endothelial Junctions to Control Mouse Embryonic Vascular Integrity. Issue 11 (20th November 2015)

• Record Type: Journal Article
• Authors: Shao, Ximing; Liu, Ke; Fan, Yi; Ding, Zhihao; Chen, Min; Zhu, Minyan; Weinstein, Lee S.; Li, Hongchang; Li, Huashun
• Is Part Of: Journal of genetics and genomics. Volume 42:Issue 11(2015:Nov.)
• Page Start: 613
• Page End: 624
• Publication Date: 2015-11-20
• Subjects: Gαs -- VE-cadherin -- S1PR1 signaling -- adherens junctions -- vascular integrity; AJ adherens junction -- CTx cholera toxin -- EC endothelial cell -- FSK Forskolin -- GPCR G protein-coupled receptor -- HUVEC human umbilical vein endothelial cell -- KD knockdown -- KO knockout -- S1PR1 sphingosine-1-phosphate receptor 1 -- VE vascular endothelial; Genetics -- Periodicals; Genomics -- Periodicals; 576.505
• DOI: 10.1016/j.jgg.2015.08.006
• Languages: English
• ISSNs: 1673-8527

Abstract

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.