EFFECT OF VASCULAR DISTENSIBILITY ON ENDOTHELIAL DEPENDENT VASOREACTIVITY

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。使年龄成为心血管（CV）疾病最重要危险因素的生理变化尚不清楚。尽管动脉僵硬和内皮功能障碍的增加伴随着年龄的增长，并与心血管风险增加有关，但它们导致心血管风险增加的机制以及僵硬/内皮功能关系的因果方向尚不清楚。最近发展的新型药物通过改变血管壁的结构成分来增加血管的扩张性（VD），现在可以探索这些关系。该建议的指导假设是，增加动脉硬度本身会损害内皮功能，而增加血管扩张的干预将改善内皮功能。特异性目的1测试VD降低是否与健康志愿者动脉内皮血流介导的血管舒张（FMD）受损有关。特异性目的2测试在扩张性降低的动脉中，内皮血管对下肢运动后搏动性增加的反应是否减弱。特异性目的3验证了VD增加可以改善血管僵硬度增加个体的FMD和运动诱导的脉冲灌注介导的血管舒张（PPMV）的假设。一种新型晚期糖基化终产物交联抑制剂将在2a期、开放标签、单盲、两个月的治疗比较中进行测试，研究VD增加对内皮功能的影响（休息时的FMD和运动诱导的PPMV）。总体目标是确定一种新的、重要的机制，即血管硬化有助于动脉粥样硬化风险，从而通过增强血管扩张性来降低这种风险。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The physiologic changes that render age the most significant risk factor for cardiovascular (CV) disease are unclear. Although increased arterial stiffness and endothelial dysfunction accompany aging and are associated with increased CV risk, the mechanisms by which they impart increased CV risk, and the causal direction of the stiffness/endothelial function relationship are unknown. The recent development of novel agents which increase vascular distensibility (VD) by altering structural components of the vessel wall now allows exploration of these relationships. The guiding hypothesis of this proposal is that increased arterial stiffness itself impairs endothelial function and that an intervention which increases vascular distensibility will improve endothelial function. Specific Aim 1 tests whether decreased VD is associated with impaired endothelial flow-mediated vasodilation (FMD) in the arteries of healthy volunteers. Specific Aim 2 tests whether the endothelial vasoactive response to increased pulsatility following lower limb exercise is diminished in arteries with reduced distensibility. Specific Aim 3 tests the hypothesis that increasing VD improves FMD and exercise-induced pulse perfusion-mediated vasodilation (PPMV) in individuals with increased vascular stiffness. A novel advanced glycation end-product crosslink breaker will be tested in a phase 2a, open label, single-blind, two month treatment comparison investigating the effect of increased VD on endothelial function (FMD at rest and exercise-induced PPMV). The overall goal is to identify a novel, important mechanism whereby vascular stiffening contributes to atherosclerotic risk, and thereby target efforts to reduce this risk by enhancing vascular distensibility.