The Proton-Sensing GPR4 Receptor Regulates Paracellular Gap Formation and Permeability of Vascular Endothelial Cells
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Krewson, Elizabeth A.
Sanderlin, Edward J.
Marie, Mona A.
Akhtar, Shayan Nik
Velcicky, Juraj
Loetscher, Pius
Yang, Li V.
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Abstract
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 endothelialcells through the Ga12/13/Rho GTPase signaling pathway. Evaluation of GPR4 in the inflammatoryresponse using the acute hindlimb ischemia-reperfusion mouse model revealed that GPR4 mediatestissue edema, inflammatory exudate formation, endothelial adhesion molecule expression, and leuko-cyte infiltration in the inflamed tissue. Genetic knockout and pharmacologic inhibition of GPR4alleviate tissue inflammation. These results suggest GPR4 is a pro-inflammatory receptor and couldbe targeted for therapeutic intervention.
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10.1016/j.isci.2020.100848