VESSEL STIFFENING, HYPERTENSION, AND VASCULAR EXTRACELLULAR MATRIX

说明（由申请人提供）：脊椎动物中传导血管的弹性性质在很大程度上由弹性蛋白与胶原蛋白的比例决定。在正常条件下，该比率由将弹性模量保持在最能够在脉动循环系统中提供电容和脉冲平滑的范围内的需要决定。这种弹性模量可以由于老化或疾病通过弹性蛋白的损失或胶原蛋白的增加而改变。其后果是血管变硬和扩张，并失去抑制血流脉动的能力。血流和血压的变化导致高血压是血管功能改变的生物标志物。这项建议是围绕着了解动脉硬化和血压变化之间的关系。目的1将利用小鼠的弹性蛋白/胶原蛋白的比例已经减少了一个副本的弹性蛋白基因的失活，研究动脉硬化和高血压的发展之间的关系。目的二利用条件性和诱导性弹性蛋白转基因改变血管壁在不同时间的弹性，探讨僵硬相关性高血压的可逆性。目标3将利用基因表达谱来识别个体基因、基因组和分子通路，这些基因、基因组和分子通路响应于血管硬度和血压的改变而改变。目标4将寻求几种治疗策略，调节血压和改变血管顺应性。 公共卫生相关性：本项目旨在阐明高血压背景下导致管道动脉硬化的机制，并在动物模型中探索动脉硬化与高血压发展之间的时间关系。

DESCRIPTION (provided by applicant): The elastic properties of conducting vessels in vertebrates are determined, to a major extent, by the ratio of elastin to collagen. Under normal conditions, this ratio is dictated by the need to maintain the elastic modulus in a range that is best able to provide capacitance and pulse smoothing in a pulsatile circulatory system. This elastic modulus can change as a result of aging or disease through the loss of elastin or an increase in collagen. The consequences are a stiffening and dilation of the vessel and loss of its ability to dampen the pulsations in blood flow. Changes in blood flow and pressure result, with hypertension being a biomarker for altered vessel function. This proposal is organized around understanding the relationship between arterial stiffening and blood pressure changes. Aim 1 will take advantage of mice where the elastin/collagen ratio has been reduced by inactivation of one copy of the elastin gene to study the relationship between arterial stiffening and the development of hypertension. Aim 2 will employ conditional and inducible elastin transgenes to change the elastic properties of the vessel wall at different times to investigate the reversibility of stiffness-related hypertension. Aim 3 will utilize gene expression profiling to identify individual genes, gene sets, and molecular pathways that change in response to vessel stiffness and alterations in blood pressure. Aim 4 will pursue several treatment strategies that modulate blood pressure and alter vessel compliance. PUBLIC HEALTH RELEVANCE: This project seeks to elucidate the mechanisms that lead to conduit artery stiffening in the context of hypertension and explore the temporal relationship between arterial stiffening and the development of hypertension in animal models.