Endothelial GPR146 promotes blood pressure elevation by impairing endothelium-dependent vasodilation

Background Hypertension remains a leading global health burden with suboptimal treatment and control rates. G-protein-coupled receptors represent major pharmacological targets for cardiovascular drug development. Our previous work demonstrated that GPR146 in vascular smooth muscle cells promotes vascular remodeling via the cAMP-CREB1-PEIZO1 signaling axis, thereby contributing to blood pressure elevation. We observed that global GPR146 deficiency mitigated angiotensin II (AngII)-induced endothelial dysfunction. However, the specific role of endothelial GPR146 in endothelial function and blood pressure regulation has not been fully elucidated. Purpose To determine the role and underlying mechanisms of endothelial GPR146 in regulating endothelium-dependent vasodilation and AngII-induced blood pressure elevation. Methods In vivo, endothelial cell-specific Gpr146 knockout mice were generated to assess blood pressure responses under AngII stimulation. Endothelium-dependent and endothelial-independent vasodilation responses were evaluated using wire myography. In vitro, GPR146 was knocked down or overexpressed in human umbilical vein endothelial cells (HUVECs) using adenoviral vectors. Endothelial nitric oxide synthase (eNOS) phosphorylation and nitric oxide (NO) production were quantified. Results In vivo, endothelial Gpr146 deletion attenuated AngII-induced blood pressure elevation compared with wild-type controls. Wire myography revealed that endothelial Gpr146 deficiency significantly improved endothelium-dependent vasodilation under AngII challenge, whereas endothelium-independent vasodilatation was not significantly altered. In vitro, GPR146 knockdown in HUVECs significantly increased phosphorylation at the activating site Ser1177 and enhanced NO production, while decreasing phosphorylation at the inhibitory site Thr495. Conversely, GPR146 overexpression reduced eNOS Ser1177 phosphorylation and NO generation, accompanied by increased Thr495 phosphorylation. Conclusion Endothelial GPR146 exacerbates AngII-induced hypertension by impairing endothelium-dependent vasodilation, likely through suppression of eNOS activation and NO bioavailability. These findings extend our previous work on GPR146-mediated vascular remodeling and support GPR146 as a potential therapeutic target for hypertension.