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

Ximing Shao^{a, b, c, #},
Ke Liu^{a, b, c, #},
Yi Fan^{a, b},
Zhihao Ding^c,
Min Chen^f,
Minyan Zhu^d,
Lee S. Weinstein^f,
Hongchang Li^{c
, ,},
Huashun Li^{a, b, d, e
, ,}

a.
West China Developmental and Stem Cell Institute, West China Second Hospital, Sichuan University, Chengdu 610041, China
b.
State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu 610041, China
c.
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
d.
SARITEX Center for Stem Cell Engineering Translational Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200123, China
e.
Nerdbio Inc., SIP Biobay, Suzhou 215213, China
f.
National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA

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Corresponding author: E-mail address: hc.li@siat.ac.cn (Hongchang Li); E-mail address: huashunli@tongji.edu.cn (Huashun Li)

These authors contributed equally to this work.

摘要

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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 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 Gα_s in mice causes early embryonic lethality with massive hemorrhage and a disorganized vasculature. The immunostaining 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 Gα_s depletion blocks the S1PR1-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.
- VE-cadherin /
- S1PR1 signaling /
- adherens junctions /
- vascular integrity
These authors contributed equally to this work.
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doi: 10.1016/j.jgg.2015.08.006

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

Corresponding author: E-mail address: hc.li@siat.ac.cn (Hongchang Li); E-mail address: huashunli@tongji.edu.cn (Huashun Li)

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doi: 10.1016/j.jgg.2015.08.006

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

Corresponding author: E-mail address: hc.li@siat.ac.cn (Hongchang Li); E-mail address: huashunli@tongji.edu.cn (Huashun Li)

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