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

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. Herein, we report that acidosis-induced GPR4 activation increases paracellular gap formation and permeability of vascular endothelia...

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Autores principales: Krewson, Elizabeth A., Sanderlin, Edward J., Marie, Mona A., Akhtar, Shayan Nik, Velcicky, Juraj, Loetscher, Pius, Yang, Li V.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2020
Materias:
Article
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6997876/
https://www.ncbi.nlm.nih.gov/pubmed/32058960
http://dx.doi.org/10.1016/j.isci.2020.100848
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author Krewson, Elizabeth A.
Sanderlin, Edward J.
Marie, Mona A.
Akhtar, Shayan Nik
Velcicky, Juraj
Loetscher, Pius
Yang, Li V.
author_facet Krewson, Elizabeth A.
Sanderlin, Edward J.
Marie, Mona A.
Akhtar, Shayan Nik
Velcicky, Juraj
Loetscher, Pius
Yang, Li V.
author_sort Krewson, Elizabeth A.
collection PubMed
description 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. Herein, we report that acidosis-induced GPR4 activation increases paracellular gap formation and permeability of vascular endothelial cells through the G(α12/13)/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.
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spelling pubmed-69978762020-02-10 The Proton-Sensing GPR4 Receptor Regulates Paracellular Gap Formation and Permeability of Vascular Endothelial Cells Krewson, Elizabeth A. Sanderlin, Edward J. Marie, Mona A. Akhtar, Shayan Nik Velcicky, Juraj Loetscher, Pius Yang, Li V. iScience Article 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. Herein, we report that acidosis-induced GPR4 activation increases paracellular gap formation and permeability of vascular endothelial cells through the G(α12/13)/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. Elsevier 2020-01-17 /pmc/articles/PMC6997876/ /pubmed/32058960 http://dx.doi.org/10.1016/j.isci.2020.100848 Text en © 2020 The Author(s) http://creativecommons.org/licenses/by/4.0/ This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Krewson, Elizabeth A.
Sanderlin, Edward J.
Marie, Mona A.
Akhtar, Shayan Nik
Velcicky, Juraj
Loetscher, Pius
Yang, Li V.
The Proton-Sensing GPR4 Receptor Regulates Paracellular Gap Formation and Permeability of Vascular Endothelial Cells
title The Proton-Sensing GPR4 Receptor Regulates Paracellular Gap Formation and Permeability of Vascular Endothelial Cells
title_full The Proton-Sensing GPR4 Receptor Regulates Paracellular Gap Formation and Permeability of Vascular Endothelial Cells
title_fullStr The Proton-Sensing GPR4 Receptor Regulates Paracellular Gap Formation and Permeability of Vascular Endothelial Cells
title_full_unstemmed The Proton-Sensing GPR4 Receptor Regulates Paracellular Gap Formation and Permeability of Vascular Endothelial Cells
title_short The Proton-Sensing GPR4 Receptor Regulates Paracellular Gap Formation and Permeability of Vascular Endothelial Cells
title_sort proton-sensing gpr4 receptor regulates paracellular gap formation and permeability of vascular endothelial cells
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6997876/
https://www.ncbi.nlm.nih.gov/pubmed/32058960
http://dx.doi.org/10.1016/j.isci.2020.100848
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