GPR146 Facilitates Blood Pressure Elevation and Vascular Remodeling via PIEZO1

作者：Zhenzhen Chen, Haizeng Zhang, Wendong Li, Qianhui Ling, Wenwen Cong, Yue Deng, Ke Chen, Shuangyue Li, Changting Cui, Wenjie Wang, Bin Geng, Jun Cai · 发表于：Circulation Research · 年份：2025 · DOI：10.1161/circresaha.125.326288 · 被引用次数：14 · 研究领域：Receptor Mechanisms and Signaling、Protein Kinase Regulation and GTPase Signaling、Renin-Angiotensin System Studies

BACKGROUND: 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. METHODS: First, RNA sequencing (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 (Piezo Type Mechanosensitive Ion Channel Component 1) 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. RESULTS: 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 cont...