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

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.