Role of the vascular endothelium in erectile physiology and disease: Influence of in vivo gene transfer ofeNOS and EC-SOD
Description
Erectile dysfunction (ED) is predominately a disease of vascular origin. It is well recognized that the incidence of ED dramatically increases in men with advancing age and diabetes mellitus. Endothelial-derived nitric oxide (NO) is an important factor in cardiovascular homeostasis and erectile function. Given the impact of endothelial-derived NO in vascular biology, we hypothesized that impairment in NO synthesis from the penile endothelium cause age- and diabetes-associated-ED. Neurogenic- and endothelium-dependent erectile function was significantly impaired with advancing age and after diabetes induction with streptozotocin in Brown Norway and Sprague Dawley rats. Corporal endothelial nitric oxide synthase (eNOS) and the second messenger, cGMP, were significantly decreased in the penile vascular bed of the aged and diabetic rat suggesting reductions in erectile function are a result of impairments in the NO/cGMP system. Adenoviral gene transfer of endothelial NOS (eNOS) to the aged and diabetic rat penis restored corporal eNOS expression/activity and cGMP levels thus improving neurogenic- and endothelium-dependent erectile responses. In another series of experiments, superoxide anion formation and total superoxide dismutase (SOD) were measured in the aged and diabetic penile vascular bed. Superoxide anion formation was significantly increased in the penis of the aged and diabetic rat with no change in the antioxidant SOD. Adenoviral gene transfer of extracellular SOD (EC-SOD) to the aged and diabetic rat penis reduced corporal superoxide anion formation, peroxynitrite, and improved cGMP levels thus improving neurogenic- and endothelium-dependent erectile responses. These data suggest eNOS and EC-SOD gene transfer can improve endogenous NO production in the penis and restore erectile function In another series of experiments, RhoA/Rho-kinase expression was measured in the penile vascular bed of the diabetic rat. RhoA/Rho-kinase expression/activity were upregulated in the diabetic corpora. Adeno-associated viral gene transfer of the dominant negative RhoA mutant (T19NRhoA) reduced RhoA/Rho-kinase expression and improved eNOS expression/activity and cGMP levels thus improving neurogenic-mediated erectile function. These data imply that inhibition of RhoA/Rho-kinase improves eNOS expression/activity thus restoring erectile function in diabetes. Putative gene therapy interventions to restore eNOS expression, endothelial NO bioavailability and subsequent endothelial function may represent an exciting new therapeutic strategy for the future treatment of ED