Abstract

Genistein is a dietary isoflavone that is abundant in soy products and has been suggested to exert cardiovascular protective effects; however, its role in hypertension remains incompletely defined. Here, we investigated whether genistein ameliorates angiotensin II (Ang II)-induced hypertension and endothelial dysfunction using complementary in vivo , ex vivo , and in vitro models. The oral administration of genistein substantially attenuated Ang II-induced elevations in systolic and diastolic blood pressure in mice without affecting body weight. Histological analyses revealed that genistein alleviated aortic wall thickening and smooth muscle hypertrophy, whereas vascular reactivity assays demonstrated improved endothelium-dependent relaxation while preserving the endothelium-independent responses. In isolated murine aortic rings, genistein reversed Ang II-induced hypercontractility and restored acetylcholine-mediated vasodilation. Furthermore, in human umbilical vein endothelial cells, genistein suppressed the Ang II-induced overproduction of reactive oxygen species (ROS) and restored nitric oxide (NO) bioavailability. Mechanistically, genistein improved endothelial redox-NO coupling, accompanied by transcriptional remodeling of the redox/NO axis [e.g., suppression of nicotinamide adenine dinucleotide phosphate oxidase 4 ( NOX4 ) and nitric oxide synthase 2 ( NOS2 ) and restoration of nitric oxide synthase 3 ( NOS3 )], which is consistent with reduced ROS and enhanced NO bioavailability. Collectively, our findings identify genistein as a potent endothelial-protective agent that ameliorates Ang II-induced hypertension, highlighting its therapeutic potential in cardiovascular disease driven by vascular dysfunction.