BERKELEY, CA (UroToday.com) - The cavernous endothelium, which is located on the inner surface of the lacunar spaces in the erectile tissue, has a crucial role in regulating the tone of the underlying smooth muscle and physiologic penile erection. Recently, a link between erectile dysfunction (ED) and cardiovascular disease was uncovered and both diseases were shown to share the same risk factors, including hypercholesterolemia, hypertension, diabetes mellitus, and smoking, with endothelial cell dysfunction being the common denominator between these two conditions. Although oral phosphodiesterase (PDE)-5 inhibitors are generally effective for men with ED, such therapies do not cure underlying vasculopathy in the corpus cavernosum tissue. Therefore, development of a new therapeutic strategy that reestablishes structural and functional microvasculature in the erectile tissue is needed to cure ED.
Recently, much attention has focused on the therapeutic angiogenesis by using angiogenic factor proteins or genes and stem cells to treat ED at preclinical level. Of a variety of angiogenic factors, VEGF has been the most extensively studied. Local intracavernous delivery of VEGF gene or protein has been shown to recover erectile function in rat models of vasculogenic ED induced by castration, diabetes, or dyslipidemia. However, VEGF can promote the formation of leaky, inflamed, and unstable vessels, which greatly limits the therapeutic utility of VEGF. In comparison, angiopoietin family, such as angiopoietin-1 (Ang-1) or angiopoietin-4 (Ang-4), is a ligand for Tie-2 receptor tyrosine kinase and is known to generate non-leaky, stable, and mature blood vessels in pre- and postnatal angiogenesis. We recently reported in mouse models of type I and type II diabetic ED that a single intracavernous injection of adenovirus-mediated synthetic Ang1 gene or two successive intracavernous injections of synthetic Ang1 protein significantly increased cavernous endothelial cell proliferation, eNOS phosphorylation, and cGMP expression and decreased the production of reactive oxygen species, such as superoxide anion and peroxynitrite. These changes restored erectile function up to 4 weeks in the diabetic mice. Interestingly, two successive administrations of synthetic Ang1 protein induced similar improvement in erectile function in the diabetic mice as compared with those who received a single injection of synthetic Ang1 gene. We also documented the efficacy of local Ang-4 protein therapy in a mouse model of diabetic ED.
Although many studies have so far demonstrated promising results targeting therapeutic angiogenesis in a variety of animal models of ED, we are not yet at the point of beginning human trial. As a result of our efforts and the efforts of other researchers to identify the novel molecules that promote healthy cavernous angiogenesis, we believe that therapeutic angiogenesis will soon open a new avenue for curing human ED.
Jun-Kyu Suh, MD, PhD as part of Beyond the Abstract on UroToday.com. This initiative offers a method of publishing for the professional urology community. Authors are given an opportunity to expand on the circumstances, limitations etc... of their research by referencing the published abstract.
National Research Center for Sexual Medicine and Department of Urology, Inha University School of Medicine, Incheon 400-711, Korea