Xu, JieMathur, JayantiVessières, EmilieHammack, ScottNonomura, KeikoFavre, JulieGrimaud, LindaPetrus, MattFrancisco, AllainLi, JingyuanLee, VanXiang, Fu-LiMainquist, James K.Cahalan, Stuart M.Orth, Anthony P.Walker, John R.Ma, ShangLukacs, ViktorBordone, LauraBandell, MichaelLaffitte, BryanXu, YanChien, ShuHenrion, DanielPatapoutian, Ardem2019-08-022019-08-022018-04-19Xu, J., Mathur, J., Vessières, E., Hammack, S., Nonomura, K., Favre, J., … Patapoutian, A. (2018). GPR68 Senses Flow and Is Essential for Vascular Physiology. Cell, 173(3), 762–775.e16. doi:10.1016/j.cell.2018.03.076https://hdl.handle.net/1805/20140Mechanotransduction 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.en-USPublisher PolicyGPCRBlood flowMechanosensationMechanotransductionOutward remodelingShear stressVascular biologyVasodilationArticle