VESSEL STIFFENING, HYPERTENSION, AND VASCULAR EXTRACELLULAR MATRIX

描述(申请人提供)：脊椎动物传导血管的弹性性质在很大程度上由弹性蛋白与胶原的比率决定。在正常情况下，这一比率取决于将弹性模数保持在最能在脉动循环系统中提供电容和脉冲平滑的范围内的需要。这种弹性模数可能会因衰老或疾病而改变，因为弹性蛋白的丧失或胶原蛋白的增加。结果是血管僵硬和扩张，失去了抑制血流脉动的能力。血流和压力的变化是结果，高血压是血管功能改变的生物标志物。这项建议是围绕着理解动脉硬化和血压变化之间的关系来组织的。目的1将利用弹性蛋白基因的一个拷贝失活导致弹性蛋白/胶原比率降低的小鼠来研究动脉硬化与高血压的发展之间的关系。目的2利用条件性和诱导性弹性蛋白转基因技术改变血管壁不同时间的弹性性质，以探讨僵直相关性高血压的可逆性。AIM 3将利用基因表达谱来识别随着血管僵硬和血压变化而改变的单个基因、基因组和分子途径。Aim 4将采取几种治疗策略来调节血压和改变血管顺应性。 公共卫生相关性：该项目试图在高血压的背景下阐明导致导管动脉硬化的机制，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.