Loss of TGF beta, apoptosis, and Bcl-2 in erectile dysfunction and upregulation of p53 and HIF-1 alpha in diabetes-associated erectile dysfunction

Vasculogenic erectile dysfunction (ED) is associated with collagen replacem ent of the cavernosal smooth muscle, mediated by an increase in transformin g growth factor (TGF)-production secondary to hypoxemia. We tested the hypo thesis that human ED is the result of an increase in apoptosis of the caver nosal smooth muscle cells with replacement by collagen, mediated by the TGF beta upregulation. We also examined the tissue for proteins associated wit h apoptosis. Human cavernosal tissue was procured from impotent men at the time of prosthesis insertion. Normal corpous cavernosum served as a control . The TUNEL assay was used to assess apoptosis, Immunohistochemistry staini ng was used to detect TGF beta and Bcl-2 expression, while Western blot ana lysis was used to detect expression of Bcl-2, p53, and hypoxia-inducible fa ctor (HIF)-1 alpha. Immunohistochemistry showed downregulation of TGF beta protein expression in the corpus cavernosum of men with ED. Apoptotic nucle i were noted in cavernosal smooth muscle from a potent man but were not fou nd in cavernosal tissue from men with ED. To gain insight into the possible mechanism of apoptosis in men with ED, the proto-oncogene Bcl-2, a potenti al inhibitor of apoptosis, was examined. Both immunohistochemistry and West ern analysis revealed the presence of Bcl-2 in the cavernosal nerve of a po tent man but its absence in cavernosal tissue from men with ED. Thus, loss of Bcl-2 expression correlated with the loss of apoptosis, In contrast, Wes tern blotting demonstrated upregulation of p53 and HIF-1 alpha expression i n the cavernosal tissues from the men with ED and diabetes. Male ED follows an active process characterized by a loss of TGF beta expression, apoptosi s, and Bcl-2 expression. However, there is upregulation of p53 and HIF-1 al pha in men with diabetes. These data support the possibility of hypoxia-med iated ED in diabetes via upregulation of p53 and HIF-1 alpha but does not s ubstantiate a role for TGF beta in ED.