GPR4

GPR4 is a proton-sensing G-protein-coupled receptor that is highly expressed in vascular endothelial cells. And GPR4 has emerged as a key regulator of inflammatory responses. GPR4 can be activated by acidosis which is a microenvironment hallmark of numerous pathological conditions such as inflammation, ischemia, and tumors. GPR4 plays a pro-inflammatory role in various pathological conditions. Activation of GPR4 by acidosis stimulates the expression of inflammatory chemokines, cytokines, adhesion molecules and the NF-κB pathway in endothelial cells, increases endothelium-leukocyte adhesion, and facilitates leukocyte infiltration. Moreover, activation of GPR4 by acidosis promotes the endoplasmic reticulum (ER) stress response and apoptosis of endothelial cells. In addition, some studies have demonstrated that GPR4 can promote angiogenesis at acidic pH and is capable of regulating the tube formation, migration, and proliferation of endothelial cells. GPR4 knockout mice displayed altered vessel morphology and reduced vascular length and density.