Metabolic and Ischemic Stress Synergistically Drive Time-Dependent Progression of Vasculogenic Erectile Dysfunction in a Rat Model

Background 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 aimed to delineate the temporal dynamics of functional impairment, structural remodeling, and molecular alterations using two rat models: high-fat diet (HFD) and HFD combined with iliac artery cuff placement (HFD + Surgery), evaluating them at weeks 4, 8, 12, and 16. Results The HFD + Surgery group exhibited earlier onset and more severe pathological changes than the HFD group. By week 4, early functional impairment was evident, marked by downregulation of endothelial nitric oxide synthase (eNOS) and calponin. From week 8, we observed reduced erectile function (maximal ICP/MAP ratios) and nitric oxide (NO) levels, smooth muscle phenotypic transition, metabolic disturbances, and sustained inflammatory and oxidative stress activation. Fibrosis-driven structural remodeling commenced after week 12, characterized by significant increases in TGF-β1 expression and collagen deposition. Conclusions Our findings delineate a clear, three-stage pathological progression of vasculogenic ED: early dysfunction (weeks 4–8), phenotypic transition and metabolic disturbance (weeks 8–12), and structural remodeling (after week 12). This comprehensive analysis highlights the synergistic role of ischemia in disease progression and provides critical temporal data for identifying key mechanistic targets and optimal intervention windows.