GPR146 Facilitates Blood Pressure Elevation and Vascular Remodeling via PIEZO1

Hypertension is a prevalent chronic disease worldwide. Elevated hydrostatic pressure (HP) is the main feature of hypertension. GPCRs (G-protein-coupled receptors) are crucial for vascular tone and a significant pharmacological target for drug development. Here, we aimed to identify the key GPCR under high HP, and explore its role and mechanism in hypertension and vascular remodeling. First, RNA-seq was performed under high HP and identified the highly expressed GPCR-GPR146. Furthermore, global knockout GPR146 mice, vascular smooth muscle cell (SMC)-specific knockin and knockout GPR146 mice were used to explore its function in hypertension. Next, an HP loading system ex vivo was established to evaluate the role of GPR146 in response to HP. Vascular SMC-specific Piezo1 mice were constructed to investigate the relationship between GPR146 and PIEZO1. In vitro, GPR146-mediated downstream signaling transduction was detected by proximity ligation assay and bioluminescence resonance energy transfer. Finally, the therapeutic effect of hypertension was detected by GPR146 neutralization antibody injection. Under high HP, we identified a highly expressed GPCR-GPR146 in vascular SMCs by RNA-seq and confirmed it in the arterial media of patients with hypertension and animal models. Functionally, overexpression or deletion of Gpr146 in SMCs demonstrated that GPR146 facilitated vascular contraction, promoted vascular SMCs phenotype switching from a contractile phenotype to synthetic phenotype and proinflammation phenotype, and led to blood pressure elevation, vascular remodeling, and cardiac hypertrophy aggravation. In vitro, GPR146 was upregulated in an HP-dependent manner. Mechanistically, GPR146 is a Gαs-coupled GPCR activating the cAMP-CREB1 (cAMP response element-binding protein 1) signaling cascade. Notably, GPR146 upregulated PIEZO1 expression by enhancing CREB1 binding to the PIEZO1 promoter region. Piezo1 deletion in SMCs blocked Gpr146-induced blood pressure elevation and vascular dysfunction. GPR146 neutralization antibody injection markedly alleviates angiotensin II-induced hypertension and vascular remodeling. Collectively, GPR146 coupled with Gαs and activating the cAMP-CREB1-PIEZO1 signaling pathway contributes to hypertension and vascular remodeling. Blocking GPR146 is an effective therapeutic strategy for hypertension.