Therapeutic Angiogenesis for Erectile Dysfunction

描述（由申请人提供）： 勃起功能障碍（艾德）仅在美国就影响2500万至3000万人。勃起功能需要细胞之间和血管组织中的适当相互作用。动脉粥样硬化是血管损伤的主要原因。动脉粥样硬化的临床前模型在勃起组织中产生类似于人类中存在的解剖和功能异常。血管生成是血管从现有血管结构生长和增殖。当施用血管生成生长因子以寻求称为“治疗性血管生成”的临床益处时，已经完成了几项用于治疗缺血性心脏和/或外周动脉疾病的完整的II期人体临床试验。已经看到了令人鼓舞的结果，更多的代理人正在进入人类调查。VEGF和bFGF存在于身体组织中，但其功能知之甚少。在血管损伤的情况下，我们和其他实验室的研究表明，VEGF和/或bFGF可以改善血管反应性并逆转身体组织中有害的组织学变化。这些有益效果发生的机制还不完全清楚。这个建议的总体目标是促进我们对血管生成生长因子在身体组织中的作用的理解。核心假设是：1）在没有疾病的情况下，血管生成生长因子通过其下游活性在维持身体组织中的正常组织学和血管反应性中起作用，和2）尽管正在进行血管损伤，但用血管生成生长因子治疗导致身体组织中的短期和长期组织学和功能益处。 I.在已建立的动脉粥样硬化临床前模型中，将血管内皮生长因子蛋白表达的变化与身体组织中的组织学（即内皮和血管平滑肌含量的损失）和血管反应性异常（即内皮依赖性和内皮非依赖性舒张）的发展相关联。在血管平滑肌细胞数量减少和正常血管反应性降低之前，VEGF蛋白和信号活性（即Akt磷酸化、内皮一氧化氮合酶水平）是否发生变化？在胆固醇喂养过程中，身体组织中血管平滑肌细胞损失的潜在机制是什么？ 二.在存在胆固醇喂养的情况下，确定外源性VEGF导致VEGF信号传导活性增加，这先于组织学和血管反应性的有益变化。确定外源性VEGF治疗后，身体组织的晚期有益变化与VEGF表达增加相关。确定bFGF是否导致与VEGF给药相似的组织学、血管反应性和VEGF信号传导活性变化。 三.）建立VEGF的配体-受体相互作用，负责身体组织的治疗调节。确定bFGF治疗需要VEGF。

DESCRIPTION (provided by applicant): 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.