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Cell. 2018 Apr 19;173(3):762-775.e16. doi: 10.1016/j.cell.2018.03.076.

GPR68 Senses Flow and Is Essential for Vascular Physiology.

Author information

1
Genomics Institute of the Novartis Research Foundation, San Diego, CA 92121, USA.
2
MITOVASC Institute, CARFI Facility, CNRS UMR 6015, INSERM U1083, Angers University, Angers, France.
3
Doris Neuroscience Center, Howard Hughes Medical Institute, the Scripps Research Institute, La Jolla, CA 92037, USA.
4
Department of Obstetrics and Gynecology, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
5
Departments of Bioengineering and Medicine, and Institute of Engineering in Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
6
Doris Neuroscience Center, Howard Hughes Medical Institute, the Scripps Research Institute, La Jolla, CA 92037, USA. Electronic address: ardem@scripps.edu.

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.

KEYWORDS:

GPCR; blood flow; mechanosensation; mechanotransduction; outward remodeling; shear stress; vascular biology; vasodilation

PMID:
29677517
PMCID:
PMC5951615
[Available on 2019-04-19]
DOI:
10.1016/j.cell.2018.03.076
[Indexed for MEDLINE]

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