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 Patapoutian

doi:10.1016/j.cell.2018.03.076

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 BandellBryan Laffitte, Yan Xu, Shu Chien, Daniel Henrion, Ardem Patapoutian

Research output: Contribution to journal › Article › peer-review

133 Scopus citations

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. A GPCR is a critical sensor for fluid shear stress in blood vessels.

Original language	English (US)
Pages (from-to)	762-775.e16
Journal	Cell
Volume	173
Issue number	3
DOIs	https://doi.org/10.1016/j.cell.2018.03.076
State	Published - Apr 19 2018
Externally published	Yes

Keywords

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

ASJC Scopus subject areas

Biochemistry, Genetics and Molecular Biology(all)

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10.1016/j.cell.2018.03.076

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Xu, J., Mathur, J., Vessières, E., Hammack, S., Nonomura, K., Favre, J., Grimaud, L., Petrus, M., Francisco, A., Li, J., Lee, V., Xiang, F. L., Mainquist, J. K., Cahalan, S. M., Orth, A. P., Walker, J. R., Ma, S., Lukacs, V., Bordone, L., ... Patapoutian, A. (2018). GPR68 Senses Flow and Is Essential for Vascular Physiology. Cell, 173(3), 762-775.e16. https://doi.org/10.1016/j.cell.2018.03.076

Xu, J, Mathur, J, Vessières, E, Hammack, S, Nonomura, K, Favre, J, Grimaud, L, Petrus, M, Francisco, A, Li, J, Lee, V, Xiang, FL, Mainquist, JK, Cahalan, SM, Orth, AP, Walker, JR, Ma, S, Lukacs, V, Bordone, L, Bandell, M, Laffitte, B, Xu, Y, Chien, S, Henrion, D & Patapoutian, A 2018, 'GPR68 Senses Flow and Is Essential for Vascular Physiology', Cell, vol. 173, no. 3, pp. 762-775.e16. https://doi.org/10.1016/j.cell.2018.03.076

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title = "GPR68 Senses Flow and Is Essential for Vascular Physiology",

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. A GPCR is a critical sensor for fluid shear stress in blood vessels.",

keywords = "GPCR, blood flow, mechanosensation, mechanotransduction, outward remodeling, shear stress, vascular biology, vasodilation",

author = "Jie Xu and Jayanti Mathur and Emilie Vessi{\`e}res and Scott Hammack and Keiko Nonomura and Julie Favre and Linda Grimaud and Matt Petrus and Allain Francisco and Jingyuan Li and Van Lee and Xiang, {Fu li} and Mainquist, {James K.} and Cahalan, {Stuart M.} and Orth, {Anthony P.} and Walker, {John R.} and Shang Ma and Viktor Lukacs and Laura Bordone and Michael Bandell and Bryan Laffitte and Yan Xu and Shu Chien and Daniel Henrion and Ardem Patapoutian",

note = "Funding Information: We thank Alec Wilson, Ton Trinh, and Hai Nguyen for engineering support; Sungjoon Kim for supplying human cancer cells; Craig Mickanin for picking the siRNA library; Yufeng Zhai and Yingyao Zhou for help with siRNA screen data analysis; Zhaozhu Qiu, Buu Tu, Loren Miraglia, Sanjeev Ranade, Angelica Romero, Glenn Federe, James Watson, Teri Johnson, Rita Moran and Kathryn Spencer for assistance; and members of Patapoutian group for constructive discussions. This work was partly supported by a grant from the NIH ( NIH R01 #DE022358 to A.P.). A.P. is an investigator of the Howard Hughes Medical Institute. Funding Information: We thank Alec Wilson, Ton Trinh, and Hai Nguyen for engineering support; Sungjoon Kim for supplying human cancer cells; Craig Mickanin for picking the siRNA library; Yufeng Zhai and Yingyao Zhou for help with siRNA screen data analysis; Zhaozhu Qiu, Buu Tu, Loren Miraglia, Sanjeev Ranade, Angelica Romero, Glenn Federe, James Watson, Teri Johnson, Rita Moran and Kathryn Spencer for assistance; and members of Patapoutian group for constructive discussions. This work was partly supported by a grant from the NIH (NIH R01 #DE022358 to A.P.). A.P. is an investigator of the Howard Hughes Medical Institute. Publisher Copyright: {\textcopyright} 2018 Elsevier Inc.",

year = "2018",

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day = "19",

doi = "10.1016/j.cell.2018.03.076",

language = "English (US)",

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T1 - GPR68 Senses Flow and Is Essential for Vascular Physiology

AU - Xu, Jie

AU - Mathur, Jayanti

AU - Vessières, Emilie

AU - Hammack, Scott

AU - Nonomura, Keiko

AU - Favre, Julie

AU - Grimaud, Linda

AU - Petrus, Matt

AU - Francisco, Allain

AU - Li, Jingyuan

AU - Lee, Van

AU - Xiang, Fu li

AU - Mainquist, James K.

AU - Cahalan, Stuart M.

AU - Orth, Anthony P.

AU - Walker, John R.

AU - Ma, Shang

AU - Lukacs, Viktor

AU - Bordone, Laura

AU - Bandell, Michael

AU - Laffitte, Bryan

AU - Xu, Yan

AU - Chien, Shu

AU - Henrion, Daniel

AU - Patapoutian, Ardem

N1 - Funding Information: We thank Alec Wilson, Ton Trinh, and Hai Nguyen for engineering support; Sungjoon Kim for supplying human cancer cells; Craig Mickanin for picking the siRNA library; Yufeng Zhai and Yingyao Zhou for help with siRNA screen data analysis; Zhaozhu Qiu, Buu Tu, Loren Miraglia, Sanjeev Ranade, Angelica Romero, Glenn Federe, James Watson, Teri Johnson, Rita Moran and Kathryn Spencer for assistance; and members of Patapoutian group for constructive discussions. This work was partly supported by a grant from the NIH ( NIH R01 #DE022358 to A.P.). A.P. is an investigator of the Howard Hughes Medical Institute. Funding Information: We thank Alec Wilson, Ton Trinh, and Hai Nguyen for engineering support; Sungjoon Kim for supplying human cancer cells; Craig Mickanin for picking the siRNA library; Yufeng Zhai and Yingyao Zhou for help with siRNA screen data analysis; Zhaozhu Qiu, Buu Tu, Loren Miraglia, Sanjeev Ranade, Angelica Romero, Glenn Federe, James Watson, Teri Johnson, Rita Moran and Kathryn Spencer for assistance; and members of Patapoutian group for constructive discussions. This work was partly supported by a grant from the NIH (NIH R01 #DE022358 to A.P.). A.P. is an investigator of the Howard Hughes Medical Institute. Publisher Copyright: © 2018 Elsevier Inc.

PY - 2018/4/19

Y1 - 2018/4/19

N2 - 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.

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KW - GPCR

KW - blood flow

KW - mechanosensation

KW - mechanotransduction

KW - outward remodeling

KW - shear stress

KW - vascular biology

KW - vasodilation

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ER -

GPR68 Senses Flow and Is Essential for Vascular Physiology

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Keywords

ASJC Scopus subject areas

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