Mechanisms Underlying the Progression of Arterial Stiffness in Hypertension

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，中央动脉硬化现在是许多此类疾病的毋庸置疑的独立危险因素，包括心脏病发作、中风和终末期肾脏疾病。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、轴向预拉伸和血管周围支持，每一个因素都有分子和细胞基础，并影响系统水平的血流动力学。易于测量的临床指标，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，脉搏波速度和动脉刚度之间的关系通常是基于Moens-Korteweg方程来证明的，它几乎忽略了壁面刚度的所有关键决定因素。我们的方法是独特的，因为我们将是第一个结合转基因小鼠模型和药物干预来直接描述由于弹性纤维的完整性，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，这些信息将被整合到一个新的计算工具中，该工具将允许轴向预拉伸、血管周围支持以及最重要的是大动脉壁成分在空间和时间上的渐进式变化对血流动力学指标的影响进行首次严格评估。特别是，我们建议大动脉硬化可能从近端向远端发展，并且早期识别这种变化（例如，在脉搏波速度显著变化之前）可能允许更早的诊断，从而更有效的干预，在大动脉硬化的有害影响传播到远端肌肉动脉和最终微血管之前，这些变化可能更难在药理学上逆转。因此，我们寻求加深我们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，我们假设中央动脉变硬在很大程度上是由于循环应变引起的弹性纤维损伤或退化，这种损伤或退化可能随着时间的推移从近端动脉向远端动脉发展，因为弹性蛋白的初始空间分布和相关的壁应变。为了验证这一假设，我们将首次量化和比较3种基本小鼠模型（野生型、纤维蛋白-1缺陷型和纤维蛋白-5缺失型）的壁力学、组成和血流动力学的进行性变化，每一种小鼠模型都接受3种药物干预（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减少的转基因小鼠模型，而不是最初的弹性蛋白减少，因为这将允许量化渐进式变化，而不依赖于弹性蛋白缺乏小鼠发育过程中可能发生的代偿适应。我们预计一氧化氮的缺失（L-NAME组）将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）将在减弱壁硬化的同时分离弹性蛋白的机械损伤和化学降解的作用；抑制胶原交联（BAPN）将分离弹性蛋白对现有胶原硬度的耦合作用与新胶原沉积的作用。实验数据将用于构建、验证和验证一种新的流固相互作用模型，该模型可以精确地揭示壁面硬化的单个决定因素对系统级血流动力学的影响。一旦完成小鼠的参数化研究，将在3个人类血液动力学原型模型（青年、中年和老年人）上进行参数化研究，首次揭示渐进式壁硬化对血液动力学临床指标（如脉搏波速度、脉压和脉压波形）的影响。我们认为，单独的建模研究可以描述动脉硬化在空间和时间上的进行性增加对系统级血流动力学的影响，有可能确定早期硬化的改进指标，这可能允许早期临床干预，从而防止不可避免地发生的长期不可逆的微观结构变化。

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.