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GPR68 Senses Flow and Is Essential for Vascular Physiology

Xu, Jie and Vessieres, Emilie and Mathur, Jayanti and Hammack, Scott and Nonomura, Keiko and Favre, Julie and Grimaud, Linda and Petrus, Matthew and Francisco, Allain and Li, Jingyuan and Lee, Van and Xiang, Fuli and Mainquist, James and Cahalan, Stuart and Orth, Anthony and Walker, John and Ma, Shang and Lukacs, Viktor and Bordone, Laura and Bandell, Michael and Laffitte, Bryan and Xu, Yan and Chien, Shu and 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

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