Angiotensin (1-7) improves diabetes mellitus-induced erectile dysfunction in rats by modulating the Cav-1/eNOS...

Diabetes mellitus-induced erectile dysfunction (DMED) is a common complication of diabetes and is often associated with impaired nitric oxide (NO) signaling and increased oxidative stress. Angiotensin (1-7) (Ang (1-7)) has been reported to exert protective effects in cardiovascular and metabolic disorders; however, its role and underlying mechanisms in DMED remain incompletely understood. This study investigated whether Ang (1-7) improves erectile function in DMED through regulation of the caveolin-1 (Cav-1)/endothelial nitric oxide synthase (eNOS) signaling pathway.

A type 2 diabetes mellitus rat model was established and divided into control, diabetes mellitus (DM), DMED, DMED treated with Ang (1-7), and DMED treated with saline groups. Erectile function was evaluated by the intracavernous pressure to mean arterial pressure ratio (ICP/MAP). Cav-1, eNOS, and phosphorylated eNOS (p-eNOS Ser1177) expression in corpus cavernosum tissue was assessed by western blot. Plasma NO and peroxynitrite (ONOO^-) levels were measured by enzyme-linked immunosorbent assay. Primary rat corpus cavernosum smooth muscle cells (CCSMCs) were exposed to high glucose and treated with Ang (1-7) or methyl-β-cyclodextrin, a caveolae-disrupting agent. Protein expression, oxidative stress markers, and intracellular calcium levels were analyzed.

DMED rats exhibited reduced erectile function, decreased Cav-1 expression, reduced eNOS phosphorylation, lower NO levels, and increased ONOO^- compared with controls. Ang (1-7) treatment significantly improved erectile responses, restored Cav-1 expression and eNOS phosphorylation, increased NO production, and reduced oxidative stress. In CCSMCs, high glucose suppressed Cav-1 and p-eNOS expression, increased ONOO^- production, and disrupted calcium homeostasis. Ang (1-7) reversed these changes. Disruption of caveolae with methyl-β-cyclodextrin diminished the effects of Ang (1-7) on eNOS phosphorylation, oxidative stress, and intracellular calcium regulation.

Ang (1-7) improves erectile function in DMED rats and protects CCSMCs from high glucose-induced injury. These effects are associated with the restoration of Cav-1/eNOS signaling, enhanced NO bioavailability, reduced oxidative stress, and improved calcium homeostasis. The findings support an important role for caveolae-mediated signaling in DMED and suggest that Ang (1-7) may represent a potential therapeutic strategy for diabetic erectile dysfunction.