Therapeutic Angiogenesis for Erectile Dysfunction

描述(由申请人提供)： 勃起功能障碍(ED)仅在美国就有2500万至3000万人受到影响。勃起功能需要细胞和血管组织之间的适当相互作用。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会在勃起组织中产生与人类相似的解剖和功能异常。血管生成是指从现有的血管结构中生长和增殖的血管。当为了寻求一种被称为“治疗性血管生成”的临床益处而应用血管生成因子时，几个已完成的治疗缺血性心脏和/或外周动脉疾病的人类临床试验已经完成。已经看到了令人鼓舞的结果，越来越多的特工正在进入人类调查。血管内皮生长因子和碱性成纤维细胞生长因子存在于人体组织中，但其功能尚不清楚。在血管损伤的背景下，我们和其他实验室的研究表明，血管内皮生长因子和/或碱性成纤维细胞生长因子可以改善血管反应性，逆转体部组织的有害组织学变化。这些有益效应的发生机制尚不完全清楚。这项建议的总体目标是促进我们对血管生成生长因子在体部组织中所起作用的理解。中心假设是：1)血管生成生长因子通过其下游活性，在没有疾病的情况下，在躯体组织中发挥维持正常组织学和血管反应性的作用；2)尽管持续的血管损伤，血管新生生长因子治疗仍能在躯体组织中产生短期和长期的组织学和功能上的好处。 在已建立的动脉粥样硬化的临床前模型中，血管内皮生长因子蛋白表达的变化与小体组织的组织学发展(即内皮和血管平滑肌含量的丧失)和血管反应性异常(即内皮依赖性和非内皮依赖性松弛)相关。血管内皮生长因子蛋白和信号活性(即Akt-磷酸化、内皮型一氧化氮合酶水平)的变化是否在血管平滑肌细胞数量减少和正常血管反应性降低之前发生？在喂饲胆固醇的过程中，体部组织中血管平滑肌细胞丢失的潜在机制是什么？ 在胆固醇喂养存在的情况下，确定外源性血管内皮生长因子导致血管内皮生长因子信号活性增加，这先于组织学和血管反应性的有益变化。证实外源性血管内皮细胞生长因子治疗后体部组织的晚期有益改变与血管内皮生长因子表达的增加相关。确定碱性成纤维细胞生长因子在组织学、血管反应性和血管内皮细胞生长因子信号活性方面是否导致与应用血管内皮生长因子相似的改变。 三、)建立负责体部组织治疗调节的血管内皮生长因子的配体-受体相互作用。确定使用碱性成纤维细胞生长因子治疗需要血管内皮生长因子。

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.