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

Background: Endothelium-derived nitric oxide (NO) is an important vasodilator essential for maintaining vascular homeostasis. However, how endothelial NO synthase (eNOS) is regulated in hypertension conditions is not yet fully understood. In this study, we describe a critical role of the α2 subunit of the glycine receptor (GLRA2) in modulating eNOS signaling and blood pressure regulation. 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.