Zinc Regulates Vascular Endothelial Cell Activity Through Zinc-sensing Receptor ZnR/GPR39

Zn is an essential element for cell survival/growth, and its deficiency is linked to many disorders. Extracellular Zn concentration changes participate in modulating fundamental cellular processes such as proliferation, secretion, ion transport, and cell signal transduction in a mechanism that is not well understood. Here, we hypothesize that the Zn-sensing receptor ZnR/G protein-coupled receptor 39 (GPR39), found in tissues where dynamic Zn homeostasis takes place, enables extracellular Zn to trigger intracellular signaling pathways regulating key cell functions in vascular cells. Thus, we investigated how extracellular Zn regulates cell viability, proliferation, motility, angiogenesis, vascular tone, and inflammation through ZnR/GPR39 in endothelial cells. Knockdown of GPR39 through siRNA largely abolished Zn-triggered cellular activity changes, Ca responses, as well as the downstream activation of Gαq-PLC pathways. Extracellular Zn promoted vascular cell survival/growth through activation of cAMP and Akt as well as overexpressing of platelet-derived growth factor-α receptor and vascular endothelial growth factor A. It also enhanced cell adhesion and mobility, endothelial tubule formation, and cytoskeletal reorganization. Such effects from extracellular Zn were not observed in GPR39 endothelial cells. Zn also regulated inflammation-related key molecules such as heme oxygenase-1, selectin L, IL-10, and platelet endothelial cell adhesion molecule 1, as well as vascular tone-related prostaglandin I2 synthase and nitric oxide synthase-3. In sum, extracellular Zn regulates endothelial cell activity in a ZnR/GPR39-dependent manner and through the downstream Gq-PLC pathways. Thus, ZnR/GPR39 may be a therapeutic target for regulating endothelial activity.