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

171 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

General Biochemistry, Genetics and Molecular Biology

Access to Document

10.1016/j.cell.2018.03.076

Cite this

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

@article{658abce794d14355924a3aa3c8ec9a1b,

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 = "Publisher Copyright: {\textcopyright} 2018 Elsevier Inc.",

year = "2018",

month = apr,

day = "19",

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

language = "English (US)",

volume = "173",

pages = "762--775.e16",

journal = "Cell",

issn = "0092-8674",

publisher = "Cell Press",

number = "3",

}

TY - JOUR

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

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.

AB - 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.

KW - GPCR

KW - blood flow

KW - mechanosensation

KW - mechanotransduction

KW - outward remodeling

KW - shear stress

KW - vascular biology

KW - vasodilation

UR - http://www.scopus.com/inward/record.url?scp=85045337636&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85045337636&partnerID=8YFLogxK

U2 - 10.1016/j.cell.2018.03.076

DO - 10.1016/j.cell.2018.03.076

M3 - Article

C2 - 29677517

AN - SCOPUS:85045337636

SN - 0092-8674

VL - 173

SP - 762-775.e16

JO - Cell

JF - Cell

IS - 3

ER -

GPR68 Senses Flow and Is Essential for Vascular Physiology

Abstract

Keywords

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Cite this