The role of vascular endothelial growth factor (VEGF) in the pathogenesis of numerous complications associated with diabetes is well established. However, little is known of VEGF's role in erectile dysfunction (ED), a condition commonly experienced by diabetic men. We hypothesized that expression of VEGF, its receptors and its signaling pathway, Akt, may be altered in diabetic penile tissues and, consequently, induce expression of molecules involved in the development of ED in diabetes. The present study utilized Ostuka Long-Evans Fatty (OLETF) rats, animal models for Type II diabetes (20 weeks of age), to determine alterations, if any, in levels of VEGF, its receptors, Akt, nitric oxide synthase isoforms, and apoptosis-related molecules in the penis using immunohistochemistry, Western blotting, in situ hybridization, and real-time quantitative PCR analyses. Furthermore, penile sections were also tested for apoptosis by Tdt-mediated dUTP Nick End Labeling (TUNEL) assay. Levels of VEGF, its receptors and Akt were markedly reduced in the penises of OLEFT rats, and those of endothelial and neuronal nitric oxide synthase were expressed less abundantly. Furthermore, while anti-apoptotic markers, Bcl-2 and phosphorylated Bad, were down-regulated, pro-apoptotic markers, active caspases-3 and Bax, were up-regulated, as evidenced by the appearance of apoptotic cells in the penile tissues of OLETF rats. We propose that disruption of VEGF signaling system in the penis may play a role in the patho-physiology/genesis of diabetic ED.