VESSEL STIFFENING, HYPERTENSION, AND VASCULAR EXTRACELLULAR MATRIX

血管硬化、高血压和血管细胞外基质

• 批准号: 8145303
• 负责人: ROBERT P. MECHAM
• 金额: $ 37.55万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-20 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8145303
• 关键词: Address; Affect; Age; Aging; Animal Model; Aorta; Arteries; Biological Assay; Biological Markers; Blood Pressure; Blood Vessels; Blood flow; Cardiac; Cardiovascular system; Collagen; Computational Biology; Data; Development; Disease; Distal; Elastic Fiber; Elastin; Electric Capacitance; Essential Hypertension; Extracellular Matrix; Gene Expression; Gene Expression Profiling; Gene Mutation; Genes; Heart; Human; Hypertension; In Vitro; Individual; Lead; Measures; Mechanics; Methods; Mining; Modeling; Molecular; Molecular Profiling; Molecular Target; Mus; Pathway interactions; Patients; Pattern; Pharmacologic Substance; Physiologic pulse; Population; Property; Proteins; Pulse Pressure; Regulatory Pathway; Resistance; Staging; Symptoms; System; Testing; Time; Transgenes; Translating; Vertebrates; Work; arterial stiffness; design; hypertension treatment; in vivo; mechanical behavior; mouse model; normal aging; normotensive; novel; pressure; public health relevance; response; small molecule; therapeutic target; tool; treatment strategy

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.

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取决于弹性蛋白与胶原蛋白的比率。在正常条件下，该比率由将弹性模量维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。由于衰老或疾病，弹性蛋白的损失或胶原蛋白的增加，这种弹性模量可能会发生变化。其后果是血管僵硬和扩张，并丧失抑制血流脉动的能力。血流量和压力发生变化，高血压是血管功能改变的生物标志物。该提案是围绕了解动脉硬化和血压变化之间的关系而组织的。目标 1 将利用通过使一份弹性蛋白基因失活而降低弹性蛋白/胶原蛋白比率的小鼠来研究动脉硬化与高血压发展之间的关系。目标 2 将采用条件性和诱导性弹性蛋白转基因来改变不同时间血管壁的弹性特性，以研究与僵硬相关的高血压的可逆性。目标 3 将利用基因表达谱来识别响应血管硬度和血压变化而变化的个体基因、基因集和分子途径。目标 4 将采取多种调节血压和改变血管顺应性的治疗策略。 公共健康相关性：该项目旨在阐明导致高血压背景下导管动脉硬化的机制，并探讨动物模型中动脉硬化与高血压发展之间的时间关系。