The Proton-Sensing GPR4 Receptor Regulates Paracellular Gap Formation and Permeability of Vascular Endothelial Cells.

Elizabeth A Krewson,Edward J Sanderlin,Mona A Marie,Shayan Nik Akhtar,Juraj Velcicky,Li V Yang,Pius Loetscher

doi:10.1016/j.isci.2020.100848

Elizabeth A Krewson, Edward J Sanderlin + Show 5 more

Open Access

https://doi.org/10.1016/j.isci.2020.100848

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Journal: iScience	Publication Date: Jan 17, 2020
Citations: 24	License type: cc-by

Affiliation: East Carolina University, Novartis (Switzerland)

Abstract

SummaryGPR4 is a pH-sensing G protein-coupled receptor highly expressed in vascular endothelial cells and can be activated by protons in the inflamed tissue microenvironment. Herein, we report that acidosis-induced GPR4 activation increases paracellular gap formation and permeability of vascular endothelial cells through the Gα12/13/Rho GTPase signaling pathway. Evaluation of GPR4 in the inflammatory response using the acute hindlimb ischemia-reperfusion mouse model revealed that GPR4 mediates tissue edema, inflammatory exudate formation, endothelial adhesion molecule expression, and leukocyte infiltration in the inflamed tissue. Genetic knockout and pharmacologic inhibition of GPR4 alleviate tissue inflammation. These results suggest GPR4 is a pro-inflammatory receptor and could be targeted for therapeutic intervention.

Highlights

The endothelium is a dynamic barrier that can mediate the transvascular movement of fluids and immune cells between the peripheral blood and interstitial tissues
SUMMARY GPR4 is a pH-sensing G protein-coupled receptor highly expressed in vascular endothelial cells and can be activated by protons in the inflamed tissue microenvironment
We report that acidosisinduced GPR4 activation increases paracellular gap formation and permeability of vascular endothelial cells through the Ga12/13/Rho GTPase signaling pathway

Summary

Introduction

The endothelium is a dynamic barrier that can mediate the transvascular movement of fluids and immune cells between the peripheral blood and interstitial tissues. Previous reports note that local pH ranging from 6.0 to 7.0 is common in the microenvironments of inflamed tissues, solid tumors, and ischemic tissues (Huang and McNamara, 2004; Justus et al, 2013; Lardner, 2001; Siesjo et al, 1996). An acidic interstitial pH is an inflammatory microenvironmental factor in many pathological conditions and has been demonstrated to modulate tissue, blood vessel, and immune cell functions (Huang and McNamara, 2004; Justus et al, 2013; Lardner, 2001; Siesjo et al, 1996)

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