The Proton-Sensing GPR4 Receptor Regulates Paracellular Gap Formation and Permeability of Vascular Endothelial Cells
The Proton-Sensing GPR4 Receptor Regulates Paracellular Gap Formation and Permeability of Vascular Endothelial Cells
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DOI：
10.1016/j.isci.2020.100848
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发表时间：
2020-02-21
期刊：
影响因子：
5.8
通讯作者：
Yang, Li V.
中科院分区：
文献类型：
--
作者：
Krewson, Elizabeth A.;Sanderlin, Edward J.;Yang, Li V.
GPR 4是一种在血管内皮细胞中高度表达的pH敏感G蛋白偶联受体，可被炎症组织微环境中的质子激活。在此，我们报告说，酸中毒诱导的GPR 4激活增加细胞旁间隙的形成和血管内皮细胞的通透性通过G（α 12/13）/Rho GT3信号通路。使用急性后肢缺血-再灌注小鼠模型评估GPR 4在炎症反应中的作用，揭示GPR 4介导炎症组织中的组织水肿、炎性渗出物形成、内皮粘附分子表达和白细胞浸润。GPR 4的基因敲除和药理学抑制减轻组织炎症。这些结果表明GPR 4是一种促炎受体，可以作为治疗干预的靶点。
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(alpha 12/13)/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.