Glycine Receptor α2 Mediates Endothelium-dependent Vasodilation via Activation of eNOS Signaling

Methods

Endothelial-specific Glra2 deficient mice and the adeno-associated viral transfected mice were generated to assess the role of GLRA2 in hypertension models. Endothelium-dependent relaxation response and whole-cell patch clamp recording were determined. Results: We first demonstrated selective expression of GLRA2 in arterial endothelial cells.

Activation of GLRA2 by its ligand, glycine, effectively counteracts hypertension in a GLRA2-dependent manner. Our patient study indicated a negative correlation between plasma levels of glycine and blood pressure. Furthermore, we showed that endothelial GLRA2 regulates vasodilation by promoting NO production, rather than functioning solely as a chloride channel.

Mechanistically, GLRA2 facilitates the phosphorylation of glycogen synthase kinase-3β at Ser9, which activates the AKT/eNOS signaling pathway in the endothelium, leading to increased NO release. Conclusions: This study discovers a novel endothelial GLRA2 pathway holds significant potential for developing new strategies to control hypertension.