S1P-mediated G-protein and RhoGTPase signaling to control endothelial barrier function

The bioactive sphingolipid S1P is present in bloodplasma, bound to carrier proteins, and is involved in many physiological processes, including angiogenesis, inflammatory responses and vascular stabilization. S1P can bind to several G-protein-coupled receptors (GPCRs) activating a number of different signalling networks.

In our study, we explored these pathways by using a set of FRET-based biosensors for different RhoGTPases (Rac1, RhoA/B/C, Cdc42) as well as for heterotrimeric G-proteins in a series of live-cell imaging experiments in primary human endothelial cells.

We demonstrate that although S1P promotes the endothelial barrier function, it induces cell spreading as well as cell contraction. This phenomenon requires tight spatiotemporal control of G-protein and RhoGTpase signaling, with a key role for the S1PR1-Gαi-Cdc42 pathway.

The research was performed at Molecular Cytology (SILS-FNWI) and the van Leeuwenhoek Centre for Advanced Microscopy in collbaoration with Sanquin.  Nathalie R. Reinhard, Marieke Mastop, Taofei Yin, Yi Wu, Esmeralda K. Bosma, Theodorus W. J. Gadella Jr., Joachim Goedhart and Peter L. Hordijk. The balance between Gai-Cdc42/Rac and Ga12/13-RhoA pathways determines endothelial barrier regulation by Sphingosine-1-Phosphate. MBoC, 2017, 10.1091/mbc.E17-03-0136