Xu, Jie, Vessieres, Emilie, Mathur, Jayanti, Hammack, Scott, Nonomura, Keiko, Favre, Julie, Grimaud, Linda, Petrus, Matthew, Francisco, Allain, Li, Jingyuan, Lee, Van, Xiang, Fuli, Mainquist, James, Cahalan, Stuart, Orth, Anthony, Walker, John, Ma, Shang, Lukacs, Viktor, Bordone, Laura, Bandell, Michael, Laffitte, Bryan, Xu, Yan, Chien, Shu, Henrion, Daniel and Patapoutian, Ardem (2018) GPR68 Senses Flow and Is Essential for Vascular Physiology. Cell, 173 (3). pp. 762-775. ISSN 00928674

Abstract

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.

Item Type:	Article
Keywords:	GPR68, flow, shear stress, endothelial cells, resistance vessels, blood pressure
Date Deposited:	03 May 2018 00:45
Last Modified:	03 May 2018 00:45
URI:	https://oak.novartis.com/id/eprint/33484