Mechanisms Underlying the Progression of Arterial Stiffness in Hypertension

高血压动脉僵硬进展的机制

• 批准号: 8588345
• 负责人: Carlos Alberto Figueroa
• 金额: $ 38.61万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-30 至 2015-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8588345
• 关键词: Abdomen; Affect; Aging; Ally; Animals; Aorta; Arteries; Attenuated; Biochemical; Biological; Biomechanics; Blood Vessels; Brain; Cardiovascular Diseases; Cardiovascular Physiology; Cause of Death; Central Artery; Chemicals; Clinical; Clinical Treatment; Clinical assessments; Collagen; Collagen Fiber; Complex; Coupled; Data; Deposition; Development; Dilatation - action; Disease; Disease susceptibility; Dissection; Distal; Doxycycline; Early Diagnosis; Elastic Fiber; Elastin; End stage renal failure; Endothelium; Equation; Exhibits; FBN1; Fatigue; Fibrillar Collagen; Functional disorder; Gene Mutation; Genetic; Geometry; Growth; Heart; Human; Hypertension; Individual; Intervention; Kidney; Knockout Mice; Liquid substance; Longitudinal Studies; Matrix Metalloproteinase Inhibitor; Matrix Metalloproteinases; Measurable; Measures; Mechanics; Methods; Metric; Microfibrils; Modeling; Molecular; Motion; Mus; Muscle; Muscle Tonus; Myocardial Infarction; NG-Nitroarginine Methyl Ester; Nitric Oxide; Organ; Pathology; Peptide Hydrolases; Physiologic pulse; Play; Property; Protein-Lysine 6-Oxidase; Pulse Pressure; Resistance; Risk Assessment; Risk Factors; Role; Rupture; Smooth Muscle; Solid; Spatial Distribution; Stretching; Stroke; Structure; Study models; System; Testing; Thick; Time; Validation; Work; arterial stiffness; base; cardiovascular risk factor; computerized tools; crosslink; disability; early onset; effective intervention; endothelial dysfunction; fibulin; genome wide association study; hemodynamics; improved; indexing; inhibitor/antagonist; insight; middle age; mouse model; novel; pressure; prevent; public health relevance; simulation; tool; treatment planning

DESCRIPTION (provided by applicant): Cardiovascular disease remains the leading cause of death and disability in the USA and stiffening of central arteries is now an unquestioned independent risk factor for many such diseases, including heart attack, stroke, and end-stage renal disease. The six primary determinants of the structural stiffness of arteries are elastic fiber integrity, collagen organization, smooth muscle tone, wall thickness, axial pre-stretch, and perivascular support, each of which has a molecular and cellular basis and affects system-level hemodynamics. Easily measured clinical metrics, such as pulse wave velocity, can and must play an increasingly greater role in cardiovascular risk assessment, but we must understand much better the mechanical and biological basis for changes in such metrics. For example, the relation between pulse wave velocity and arterial stiffness is often justified based on the Moens-Korteweg equation, which ignores almost all of the key determinants of wall stiffness. Our approach is unique because we will be the first to combine genetically modified mouse models and pharmacological interventions to delineate directly the effects on the material stiffness of the wall due to the integrity of elastic fibers, organization of collagen fibers, and contractility of smooth muscle. Moreover, this information will be incorporated within a novel computational tool that will allow effects of axial prestretch, perivascular support, and most importantly spatially and temporally progressive changes in large artery wall composition on hemodynamic metrics to be rigorously assessed for the first time. In particular, we suggest that large artery stiffening likely progresses from proximal to distal large arteries and identification of the early onset of such changes (e.g., prior to marked changes in pulse wave velocity) may allow earlier diagnosis and thus more effective intervention, prior to the propagation of detrimental effects of large artery stiffening to distal muscular arteries and eventually the microvessels, changes to which may be more difficult to reverse pharmacologically. Hence, we seek to deepen our fundamental understanding of the basis of arterial stiffening and to enable better clinical assessments and treatment planning based on readily available data. Specifically, we hypothesize that central arteries stiffen due, in large part, to a cyclic-strain induced damage to or degradation of elastic fibers that likely progresses over time from proximal to distal arteries because of initial spatial distributions of elastin and associated wall strains. To test this hypothesis, we will quantify and compare for the first time progressive changes in wall mechanics, composition, and hemodynamics in 3 basic mouse models (wild-type, fibrillin-1 deficient, and fibulin-5 null), each subjected to 3 pharmacological inter- ventions (L-NAME, doxycycline, and BAPN). That is, we will use genetically modified mouse models of graded decreases in elastic fiber integrity, not initially diminished elastin, for this will allow progressive changes to be quantified independent of possible compensatory adaptations that occur during development in elastin deficient mice. We expect loss of nitric oxide (L-NAME group) to highlight a role of smooth muscle tone and exacerbate the progression of wall stiffening, diminished proteinase activity (doxycycline) to separate roles of mechanical damage and chemical degradation of elastin while attenuating wall stiffening, and inhibiting collagen cross-linking (BAPN) to separate the coupled effects of elastin on the stiffness of extant collagen from the role of new collagen deposition. The experimental data will be used to construct, verify, and validate a novel fluid-solid-interaction model that can reveal precisely the effects of individual determinants of wall stiffening on system-level hemodynamics. Once accomplished for the mouse, parametric studies will be performed on 3 prototypical models of hemodynamics in humans (young, middle-aged, and old) to reveal, for the first time, the effects of progressive wall stiffening on clinical metrics of hemodynamics such as pulse wave velocity, pulse pressure, and pulse pressure waveform. We submit that modeling studies alone can delineate effects of spatially and temporally progressive increases in arterial stiffening on system-level hemodynamics, with the potential to identify improved indicators of early stiffening that may allow an earlier clinical intervention that can prevent the longer-term irreversible changes to the microstructure that otherwise inevitably occur.

描述（由申请人提供）：心血管疾病仍然是美国死亡和残疾的主要原因，而中央动脉硬化现在无疑是许多此类疾病的独立危险因素，包括心脏病发作、中风和终末期肾病。动脉结构刚度的六个主要决定因素是弹性纤维完整性、胶原组织、平滑肌张力、壁厚度、轴向预拉伸和血管周围支撑，每个因素都具有分子和细胞基础并影响系统级血流动力学。易于测量的临床指标（例如脉搏波速度）可以而且必须在心血管风险评估中发挥越来越大的作用，但我们必须更好地了解这些指标变化的机械和生物学基础。例如，脉搏波速度和动脉硬度之间的关系通常基于 Moens-Korteweg 方程来证明，该方程忽略了壁硬度的几乎所有关键决定因素。我们的方法是独特的，因为我们将是第一个将转基因小鼠模型和药物干预相结合的人，以直接描述弹性纤维的完整性、胶原纤维的组织和平滑肌的收缩性对壁材料刚度的影响。此外，这些信息将被纳入一种新颖的计算工具中，该工具将首次严格评估轴向预拉伸、血管周围支撑以及最重要的大动脉壁成分在空间和时间上的渐进变化对血流动力学指标的影响。特别是，我们建议大动脉硬化可能从近端大动脉向远端进展，识别这种变化的早期发生（例如，在脉搏波速度显着变化之前）可能允许更早诊断，从而在治疗之前进行更有效的干预。大动脉硬化的有害影响传播到远端肌动脉并最终传播到微血管，这种变化可能更难以通过药理学来逆转。因此，我们寻求加深对动脉硬化基础的基本理解，并根据现有数据进行更好的临床评估和治疗计划。具体来说，我们假设中央动脉硬化在很大程度上是由于循环应变引起的弹性纤维损伤或降解，由于弹性蛋白和相关壁应变的初始空间分布，弹性纤维可能随着时间的推移从近端动脉到远端动脉进展。为了检验这一假设，我们将首次量化并比较 3 种基本小鼠模型（野生型、fibrillin-1 缺陷型和 fibulin-5 缺失型）中壁力学、成分和血流动力学的渐进变化，每种模型均经受 3药物干预（L-NAME、多西环素和 BAPN）。也就是说，我们将使用弹性纤维完整性逐渐降低的转基因小鼠模型，而不是最初减少的弹性蛋白，因为这将允许量化渐进的变化，独立于弹性蛋白缺陷小鼠发育过程中可能发生的补偿性适应。我们预计一氧化氮（L-NAME 组）的损失会突出平滑肌张力的作用并加剧壁硬化的进展，蛋白酶活性的降低（多西环素）可分离机械损伤和弹性蛋白化学降解的作用，同时减弱壁硬化，抑制胶原交联（BAPN），将弹性蛋白对现有胶原硬度的耦合效应与新胶原沉积的作用分开。实验数据将用于构建、验证和验证一种新型流固相互作用模型，该模型可以精确揭示壁硬化的各个决定因素对系统级血流动力学的影响。一旦在小鼠身上完成，参数研究将在人类（年轻、中年和老年）的 3 个典型血流动力学模型上进行，以首次揭示渐进性壁硬化对血流动力学临床指标的影响，例如脉搏波速度、脉压和脉压波形。我们认为，仅建模研究就可以描绘动脉硬化在空间和时间上逐渐增加对系统级血流动力学的影响，并有可能确定早期硬化的改善指标，从而可以进行早期临床干预，从而防止长期不可逆的变化到否则不可避免地发生的微观结构。