PURPOSE: We developed a novel rat model to investigate vasculogenic erectile dysfunction(ED) and investigated the possible mechanisms of atherosclerosis-induced ED. MATERIALS AND METHODS: Twenty male Sprague-Dawley rats(3 months old) were divided into control(n=10) and atherosclerosis(n=10) group. The control group was placed on a regular diet, while the atherosclerosis group received a 1% cholesterol diet for 6 weeks. To induce endothelial dysfunction, which is essential to the development of atherosclerosis, NG-nitro-l-arginine methyl ester(L-NAME) 1 mg/ml was added to the drinking water for the first 2 weeks. After six weeks, erectile function was assessed with cavernous nerve electrostimulation. Measurement of blood levels of cholesterol and histopathologic examination of the aorta and iliac artery were done. Semiquantitative RT-PCR for hypoxia-induced factor(HIF)-1alpha mRNA and Western blotting for HIF-1alpha and transforming growth factor (TGF)-beta1 were carried out on the penile tissues. RESULTS: Compared with the control group, both serum cholesterol level and arterial pressure were significantly elevated in the atherosclerosis group. The atherosclerosis group also showed prolonged and diminished erectile responses during cavernous nerve stimulation. Histologic study revealed definite atherosclerosis in the aorta and internal iliac artery, and the severity of atherosclerosis correlated well with decreased erectile function. Although RT-PCR did not show differences in the expression of HIF-1alpha mRNA, expression of HIF-1alpha and TGF-beta1 was significantly higher in the atherosclerosis group than in the control animals. CONCLUSIONS: In the rat, vasculogenic ED secondary to atherosclerosis could be generated by a high-cholesterol diet combined with an NOS inhibitor. Atherosclerosis might hamper erectile function by cavernosal ischemia secondary to a reduced blood supply and possibly by cavernosal fibrosis.