Gene therapy of diabetic penile endothelial dysfunction. Half of the 7.5 million diabetic men in the US will develop erectile dysfunction (ED). Despite advances in our understanding of erectile physiology, treatments for diabetic impotence remains limited, and phosphodiesterase-specific therapy (Viagra) fails in the majority of diabetics with ED. It is known that endothelium- dependent smooth muscle relaxation is impaired in vascular and penile tissue from diabetics. Nitric oxide generated in the endothelium is involved in vasorelaxation and is an important supporter of cardiovascular homeostasis. But the role of the endothelial cell during flaccidity and erection is not understood. We hypothesize that the endothelial cell is critical to the homeostasis of the corpus cavernosum and that iNOS gene therapy of the penile endothelium can mitigate the development of erectile dysfunction. The goals of this project are 1) to demonstrate that diabetes impairs endothelium-dependent erectile responses through changes in eNOS homeostasis and endothelial cytoskeletal organization and 2) to repair the penile endothelium with iNOS gene therapy.
Specific Aim 1 will characterize the time course and severity of endothelium dependent erection in the normal and streptozotocin- induced diabetic rat.
Specific Aims 2 and 3 will examine the effects of hyperglycemia on corporal endothelial structure and function in vitro and in vivo. Cultured corporal endothelial cells and a detailed analysis of rat and human diabetic corpora will provide different methodological approaches to characterize eNOS expression and activity, cytoskeletal integrity, and disturbances in the cell cycle.
Specific Aim 4 will determine whether transplantation of iNOS-transduced endothelial cells will generate high levels of nitric oxide, repair the corporal endothelium, and augment erectile responses in diabetic rats. By providing a more detailed understanding of the corporal endothelium, and the alterations induced by diabetes, we can develop a novel therapeutic strategy targeted to the endothelial cell and endothelium-dependent mechanisms of erectile dysfunction. Such a strategy may ultimately be beneficial to men with ED due to diabetes as well as smoking, hypercholesterolemia, and aging.
