EFFECT OF VASCULAR DISTENSIBILITY ON ENDOTHELIAL DEPENDENT VASOREACTIVITY

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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.