Mechanisms Underlying The Progression of Large Artery Stiffness in Hypertension

高血压大动脉僵硬进展的机制

• 批准号: 9249668
• 负责人: Carlos Alberto Figueroa
• 金额: $ 35.47万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-30 至 2020-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9249668
• 关键词: Abdomen; Acquired Immunodeficiency Syndrome; Address; Affect; Aging; Angiotensins; Animal Model; Anti-Inflammatory Agents; Anti-inflammatory; Aorta; Arteries; Attention; Biomechanics; Blood Vessels; Brain; Cardiovascular Diseases; Cardiovascular system; Central Artery; Chest; Chronic; Clinical; Clinical Trials; Complex; Computer Simulation; Computers; Connective Tissue Diseases; Coronary; Data; Data Set; Deposition; Development; Diabetes Mellitus; Diagnosis; Diagnostic; Disease; Distal; Elastic Fiber; Elderly; Evolution; Extracellular Matrix; FBLN5 gene; FBN1; Fibroblasts; Funding; Glean; Global Change; Goals; Gold; Healthcare; Heart; Heart Diseases; Human; Hypertension; In Vitro; Inflammation; Infusion procedures; Kidney; Kidney Failure; Liquid substance; Losartan; Marfan Syndrome; Mechanical Stress; Mechanics; Methods; Modeling; Mus; Mutation; NG-Nitroarginine Methyl Ester; Obesity; Organ; Organ Transplantation; Oxidative Stress; Paper; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacological Treatment; Phenotype; Physiologic pulse; Physiological; Population; Property; Pulse Pressure; Resistance; Role; Smooth Muscle; Societies; Sodium Chloride; Solid; Stimulus; Structure; Testing; Therapeutic; Time; Transplant Recipients; Variant; Work; arterial stiffness; base; clinically translatable; design; diabetic; disorder risk; drug efficacy; endothelial dysfunction; experience; hemodynamics; improved; in vivo; indexing; innovation; insight; kidney vascular structure; mouse model; neurovascular; novel; public health relevance; receptor; regional difference; tempol

 DESCRIPTION (provided by applicant): Stiffening of central arteries (i.e., the aorta and carotids) is now recognized as a strong indicator and initiator of cardiovascular, neurovascular, and renovascular diseases. Active searches are underway both to identify the best clinical metric of increased arterial stiffness and to find "de-stiffening" drugs that can lower disease ris. Amongst the metrics considered, carotid-femoral pulse wave velocity (cf-PWV) has emerged as the gold standard for assessing stiffness and the potential efficacy of de-stiffening drugs. Yet, given that arteries stiffen differentially by region and that cf-PWV yields information that is necessarily averaged over a large portion of the central vasculature, we submit that there is a need to assess better its potential as an early indicator of arterial stiffening. That is, it may b that by the time cf-PWV increases to a diagnostic value, underlying structural and mechanical changes may be largely entrenched and thereby less amenable to treatment. The goals of this project are to build on a very successful first 4-year funding period (25 papers + 10 expected soon) and to quantify and compare, for the first time, the progression of regional differences in large artery stiffening in four diverse mouse models that collectively address four key aspects of human hyper- tension, namely, endothelial dysfunction, effects of salt loading, and excess systemic vs. local angiotensin-II. These models also depend, in part, on inflammation, which is increasingly recognized as an important contributor to hypertension and vascular aging. Progressive, regional, stiffening of 5 arteries (carotid, descending thoracic, suprarenal abdominal, infrarenal abdominal, and iliac) will be quantified via in vivo data as well as novel computer-controlled in vitro biaxial tests. These data, in turn, will be used to extend and inform novel fluid-solid-interaction computational model that will be validated with available data and then used to assess the effects of evolving regional differences in wall properties on cf-PWV and, importantly, the pulse pressures at the levels of the heart and kidney. It is, of course, the increased pulse pressures in the coronary and renal vasculature that is the true concern of hypertension. Finally, we will also assess the potential efficacy of two drugs, an angiotensin-II type 1 receptor antagonist and an anti-inflammatory agent, again using the most comprehensive structural, mechanical, and hemodynamic assessments to date. This project is highly significant for it will reveal unprecedented insight into fundamental structural and mechanical mechanisms that underlie central arterial stiffening and its effects on central hemodynamics, which is increasingly important to large segments of our society - hypertensive, the elderly, diabetics, the obese, transplant recipients, and even those treated for AIDS. This project is innovative for i will couple novel experimental methods and computational models to study together four different mouse models that represent a broad spectrum of contributors to human hypertension as well as the efficacy of two potential treatments of both.

 描述（由申请人提供）：中央动脉（即主动脉和颈动脉）硬化现在被认为是心血管、神经血管和肾血管疾病的强有力的指标和引发因素，目前正在进行积极的搜索，以确定增加的最佳临床指标。动脉硬化并寻找可以降低疾病风险的“去硬化”药物 在考虑的指标中，颈动脉-股动脉脉搏波速度 (cf-PWV) 具有重要意义。成为评估僵硬度和去僵硬药物潜在功效的黄金标准。然而，考虑到动脉硬化程度因区域而异，并且 cf-PWV 产生的信息必然是大部分中央脉管系统的平均值，因此我们认为：有必要更好地评估其作为动脉硬化早期指标的潜力，也就是说，当 cf-PWV 增加到诊断值时，潜在的结构和机械变化可能会在很大程度上根深蒂固，并且可能会发生。该项目的目标是建立在非常成功的第一个 4 年资助期（25 篇论文+预计很快将有 10 篇）的基础上，并首次量化和比较大动脉区域差异的进展。四种不同的小鼠模型中的僵硬共同解决了人类高血压的四个关键方面，即内皮功能障碍、盐负荷的影响以及全身血管紧张素-II 与局部血管紧张素 II 的过量。被越来越多地认可为5 种动脉（颈动脉、降胸动脉、肾上动脉、肾下腹动脉和髂动脉）的进行性局部硬化将通过体内数据以及新型计算机控制的体外双轴测试进行量化。反过来，这些数据将用于扩展和告知新型流固相互作用计算模型，该模型将使用可用数据进行验证，然后用于评估不断变化的壁特性区域差异的影响。 cf-PWV，重要的是心脏和肾脏的脉压。当然，冠状动脉和肾脏脉管系统的脉压增加才是高血压的真正问题。再次使用迄今为止最全面的结构、机械和血流动力学评估，研究两种药物（血管紧张素-II 1 型受体拮抗剂和抗炎药）的潜在功效。该项目非常重要，因为它将揭示对基本原理的前所未有的见解。结构和机械机制它是中央动脉硬化的基础及其对中央血流动力学的影响，这对我们社会的大部分人来说越来越重要——高血压、老年人、糖尿病患者、肥胖者、移植接受者，甚至艾滋病治疗者。这个项目对于我来说是创新的。将新颖的实验方法和计算模型结合起来，共同研究四种不同的小鼠模型，这些模型代表了人类高血压的广泛影响因素，以及两种潜在治疗方法的功效。