Mas‐Related G Protein‐Coupled Receptor Member D Sustains Hypertension

ABSTRACT Hypertension and its associated complications, including vascular remodeling, pose a major burden on global public health. However, the role of Mas‐related G protein‐coupled receptor member D (MrgD) in hypertension remains incompletely understood. In this study, we observed upregulated MrgD expression in the arterial tissues of hypertensive patients and animal models. In Sprague‐Dawley rats, MrgD overexpression elevated blood pressure (BP) and promoted mesenteric vascular remodeling, whereas MrgD knockdown in spontaneously hypertensive rats normalized BP and ameliorated vascular remodeling. Consistently, MrgD knockout mice exhibited resistance to angiotensin II (Ang II)‐induced hypertension and vascular injury. Mechanistic investigations demonstrated that MrgD facilitated vascular remodeling in vascular smooth muscle cells (VSMCs) through the voltage‐gated L‐type Ca 2 + channel (Cav1.2)‐Ca 2 + /calmodulin‐dependent protein kinase IIγ (CaMKIIγ) signaling axis. Co‐immunoprecipitation coupled with mass spectrometry and in vitro functional assays confirmed that Ang II enhanced the interaction among MrgD, CaMKIIγ, and Cav1.2, thereby promoting VSMC phenotypic switch. Through artificial intelligence‐driven screening combined with functional validation, we identified risperidone as a small‐molecule inhibitor of MrgD that effectively attenuated hypertension and vascular remodeling. These findings established MrgD as a key contributor to the pathogenesis of hypertension and underscore its potential as a promising therapeutic target for hypertension and its associated vascular complications.