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.

GPR4是一种pH敏感的G蛋白偶联受体，在血管内皮细胞中高度表达，可以被发炎的组织微环境中的质子激活。在此，我们报道酸中毒诱导的GPR4激活通过Gα12 _{/ 13}增加了血管内皮细胞的旁细胞间隙形成和通透性/ Rho GTPase信号通路。使用急性后肢缺血再灌注小鼠模型评估GPR4在炎症反应中的作用，发现GPR4介导了组织水肿，炎症渗出液形成，内皮粘附分子表达以及发炎组织中的白细胞浸润。GPR4的基因敲除和药理抑制可减轻组织炎症。这些结果表明，GPR4是促炎性受体，可以作为治疗干预的靶点。