Metabolic and vascular stress drive progression of erectile dysfunction in a rat model

Erectile dysfunction (ED) is a common male sexual disorder, with the vasculogenic subtype primarily driven by endothelial injury and metabolic dysfunction. Current research often lacks a systematic, time-course analysis of its progressive pathology. We performed a 16-week time-course analysis in rats fed a HFD or HFD combined with bilateral iliac artery cuff placement (HFD + Surgery) to characterize functional decline, tissue remodeling, and molecular changes. Both models developed progressive dyslipidemia and systemic inflammation, evidenced by increased TG, TC, and LDL-C and elevated serum IL-6 and TNF-α. Compared with HFD alone, HFD + Surgery exhibited an earlier onset and greater severity of disease features. Erectile function declined over time, reflected by reduced Max ICP/MAP ratios and impaired mating performance. In penile tissue, combined metabolic and vascular stress was accompanied by an intensified inflammatory–oxidative milieu, with increased IL-6, TNF-α, and MDA together with reduced GSH and SOD. Endothelial dysfunction was supported by reduced NO bioavailability, a reduced p-eNOS/eNOS ratio, and diminished CD31 signals. Concurrently, smooth muscle remodeling was consistent with a profibrotic, synthetic shift, with increased TGF-β and OPN and decreased calponin and α-SMA. These alterations were accompanied by more pronounced cavernosal fibrosis, manifested by a lower smooth muscle-to-collagen ratio. Vasculogenic ED progressed in stages: metabolic–inflammatory priming (weeks 4–8), functional deterioration with phenotypic shift (weeks 8–12), and fibrotic remodeling (after week 12). Superimposed pelvic arterial stress was associated with earlier onset and greater severity, informing target prioritization and intervention windows.