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(即大动脉和颈动脉)硬化现在被认为是心血管、神经血管和肾血管疾病的强烈指标和始发者。积极的研究正在进行中，既是为了确定动脉僵硬增加的最佳临床指标，也是为了寻找可以降低疾病RIS的“去僵硬”药物。在考虑的指标中，颈动脉-股动脉脉搏波速度(cf-pwv)已成为评估僵硬和去僵化药物潜在疗效的金标准。然而，考虑到动脉硬化的区域不同，并且cf-pwv所产生的信息在很大一部分中央血管系统中必然是平均的，我们认为有必要更好地评估其作为动脉硬化的早期指标的潜力。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在很大程度上是根深蒂固的，因此不太适合治疗。这个项目的目标是建立一个非常成功的第一个4年资助期(25篇论文+10篇预计很快)，并首次量化和比较四种不同的小鼠模型中大动脉硬化的区域差异进展，这四种模型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，以及全身和局部血管紧张素-II过剩。这些模型还在一定程度上依赖于炎症，炎症越来越被认为是高血压和血管老化的重要因素。5条动脉(颈动脉、胸降支、肾上腹动脉、肾下腹动脉和髂动脉)的渐进性、区域性、硬化性将通过活体数据和新的计算机控制的体外双轴测试进行量化。这些数据反过来将被用来扩展和提供新的流固相互作用计算模型，该模型将用现有数据进行验证，然后用于评估壁属性变化的区域差异对cf-pwv的影响，更重要的是，评估心脏和肾脏水平的脉压。当然，冠状动脉和肾血管的脉压升高才是高血压的真正问题。最后，我们还将使用迄今为止最全面的结构、机械和血流动力学评估来评估两种药物的潜在疗效，一种是血管紧张素Ⅱ1型受体拮抗剂，另一种是抗炎药。这个项目意义重大，因为它将揭示出对中央动脉硬化背后的基本结构和机械机制及其对中心血流动力学的影响的前所未有的洞察，中心血流动力学对我们社会的大部分人--高血压、老年人、糖尿病患者、肥胖者、移植接受者，甚至是那些接受艾滋病治疗的人--越来越重要。这个项目是创新的，因为我将结合新的实验方法和计算模型一起研究四个不同的小鼠模型，这四个模型代表了导致人类高血压的广泛因素，以及两种潜在治疗方法的疗效。