VESSEL STIFFENING, HYPERTENSION, AND VASCULAR EXTRACELLULAR MATRIX

描述（由申请人提供）：脊椎动物传导血管的弹性特性在很大程度上由弹性蛋白与胶原蛋白的比例决定。在正常情况下，这个比率是由需要保持弹性模量在一个范围内，这是最好的能够提供电容和脉冲平滑脉动循环系统。这种弹性模量可以由于衰老或疾病而改变，通过弹性蛋白的损失或胶原蛋白的增加。其后果是血管的僵硬和扩张，并失去其抑制血流脉动的能力。结果是血流和血压的改变，高血压是血管功能改变的生物标志物。这一建议是围绕理解动脉硬化和血压变化之间的关系而提出的。目的1将利用弹性蛋白/胶原比例因一个弹性蛋白基因副本失活而降低的小鼠来研究动脉硬化与高血压发展之间的关系。目的2将采用条件和诱导弹性蛋白转基因在不同时间改变血管壁的弹性特性，以研究刚性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、基因集和分子途径，这些基因、基因集和分子途径会随着血管硬度和血压的变化而变化。目的4将探讨几种调节血压和改变血管顺应性的治疗策略。

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.