GPR68 Senses Flow and Is Essential for Vascular Physiology
Jie Xu, Jayanti Mathur, Emilie Vessières, Scott Hammack, Keiko Nonomura, Julie Favre, Linda Grimaud, Matt Petrus, Allain Francisco, Jingyuan Li, Van Lee, Fu li Xiang, James K. Mainquist, Stuart M. Cahalan, Anthony P. Orth, John R. Walker, Shang Ma, Viktor Lukacs, Laura Bordone, Michael Bandell, Bryan Laffitte, Yan Xu, Shu Chien, Daniel Henrion, Ardem PatapoutianCell2018
Mechanotransduction plays a crucial role in vascular biology. One example of this is the local regulation of vascular resistance via flow-mediated dilation (FMD). Impairment of this process is a hallmark of endothelial dysfunction and a precursor to a wide array of vascular diseases, such as hypertension and atherosclerosis. Yet the molecules responsible for sensing flow (shear stress) within endothelial cells remain largely unknown. We designed a 384-well screening system that applies shear stress on cultured cells. We identified a mechanosensitive cell line that exhibits shear stress-activated calcium transients, screened a focused RNAi library, and identified GPR68 as necessary and sufficient for shear stress responses. GPR68 is expressed in endothelial cells of small-diameter (resistance) arteries. Importantly, Gpr68-deficient mice display markedly impaired acute FMD and chronic flow-mediated outward remodeling in mesenteric arterioles. Therefore, GPR68 is an essential flow sensor in arteriolar endothelium and is a critical signaling component in cardiovascular pathophysiology. A GPCR is a critical sensor for fluid shear stress in blood vessels.