Erectile dysfunction (ED) effects 25 - 30 million people in the US alone. Erectile function requires the proper interactions between cells and in vascular tissue. Atherosclerosis is leading cause of vascular injury. Pre-clinical models of atherosclerosis produce anatomic and functional abnormalities in erectile tissue that are similar to those present in humans. Angiogenesis is the growth and proliferation of blood vessels from existing vascular structures. When angiogenic growth factors are administered in order to seek a clinical benefit that is termed """"""""therapeutic angiogenesis"""""""" and several completed Phase II human clinical trials for treating ischemic heart and/or peripheral arterial disease have been completed. Encouraging results have been seen and more agents are entering human investigation. VEGF and bFGF are present in corporal tissues but their function is poorly understood. In the setting of vascular injury, studies from our and other laboratories have shown that the VEGF and/or bFGF can improve vasoreactivity and reverse detrimental histological changes in corporal tissue. The mechanisms by these beneficial effects occur is not completely understood. The overall goal of this proposal is to advance our understanding of the role angiogenic growth factors have in corporal tissue. The central hypotheses are: 1) angiogenic growth factors through their downstream activity play a role in maintaining normal histology and vasoreactivity, in corporal tissue, in the absence of disease and 2) therapy with angiogenic growth factors leads to short- and long-term histological, and functional, benefits in corporal tissue despite ongoing vascular injury. I. In an established pre-clinical model of atherosclerosis, correlate changes in vascular endothelial growth factor protein expression with the development of histological (i.e. loss of endothelial and vascular smooth muscle content) and vasoreactivity abnormalities (i.e. endothelial dependent and endothelial independent relaxation) in corporal tissue. Do changes in VEGF protein and signaling activity (i.e. Akt-phosphorylation, endothelial nitric oxide synthase levels) occur before there is a loss of vascular smooth muscle cell number and a reduction in normal vasoreactivity? What are the potential mechanisms for the loss of vascular smooth muscle cells in corporal tissue during cholesterol feeding? II. In the presence of cholesterol feeding, establish that exogenous VEGF leads to increases in VEGF signaling activity that precede the beneficial changes in histology and vasoreactivity. Establish that the late beneficial changes in corporal tissue that follow exogenous VEGF therapy are correlated with increases in VEGF expression. Establish whether bFGF results in similar changes on histology, vasoreactivity, and VEGF signaling activity as VEGF administration. III.) Establish the ligand-receptor interactions for VEGF that are responsible for the therapeutic modulation of corporal tissue. Establish that therapy with bFGF requires VEGF.
| Xie, Donghua; Odronic, Shelley I; Wu, Feihua et al. (2007) Mouse model of erectile dysfunction due to diet-induced diabetes mellitus. Urology 70:196-201 |
