Micro-Mechanical Role of Hypertension in Intimal Hyperplasia

描述(由申请人提供)：机械应力和应变在高血压和动脉粥样硬化形成中的作用被广泛接受。这项建议的目的是开发一个经过验证的健康和高血压患者冠状动脉整个血管壁的微观结构模型(作为内膜增生的机械刺激，IH)。该方案包括原位多光子显微镜(MPM)，它能够三维描绘机械载荷下冠状动脉的弹性蛋白、胶原和平滑肌细胞(SMC)，实验方法来量化冠状动脉壁的层状结构，利用非线性力学的数值算法，以及现代计算能力来处理复杂的微结构几何和边界条件。因此，本文的具体目标是：1)建立基于成分超微结构(纤维和SMC)的冠状动脉壁被动和主动本构模型；2)验证Aim 1的完整动脉壁本构模型。 使用(宏观)三轴力学试验的被动和主动数据和微观结构变形的原位成像；以及3)使用AIM 2的验证模型并结合有限元分析和实验验证来阐明高血压对高血压病的力学作用。我们已经建立了三轴力学测试(膨胀、拉伸和扭转)、原位微结构成像、图像处理和重建的方法，并开发了一种新的预测外膜的细观力学模型。在这里，我们建议将这些进展扩展到整个血管壁，以提供一个经过验证的虚拟血管模型，该模型可以用于定量验证各种假说(例如，高血压在IH中的作用)。所提出的基于微结构的计算框架的成功将为冠状动脉的结构-功能关系提供准确可靠的数学描述，并导致对血管力学响应的新的理解水平。此外，健康人和高血压患者(包括高血压患者)的显微结构及其变形的大量定量实验数据将极大地丰富对纤维和SMC的力学环境以及动脉粥样硬化形成中的重塑过程的理解。

DESCRIPTION (provided by applicant): The roles of mechanical stresses and strains in hypertension and atherogenesis are well accepted. The objective of this proposal is to develop a validated micro-structural model of the entire vessel wall of coronary arteries in health and hypertension (as a mechanical stimulus for intimal hyperplasia, IH). The proposal involves in situ Multi-Photon Microscopy (MPM) that enables the 3-D depiction of elastin, collagen and smooth muscle cells (SMC) of the coronary artery under mechanical loading, experimental approach to quantify the layered structure of the wall, numerical algorithm that takes advantage of nonlinear mechanics, and modern computational capability to deal with the complex micro-structural geometry and boundary conditions. Accordingly, the Specific Aims are: 1) To develop a passive and active constitutive model for coronary arterial wall based on constituent ultrastructure (fibers and SMC); 2) To validate the full constitutive arterial wall model of Aim 1 using both passive and active data of (macroscopic) triaxial mechanical tests and in situ imaging of the microstructural deformation; and 3) To elucidate the mechanical role of hypertension on IH using the validated models of Aim 2 combined with finite element analysis and experimental validation. We have previously established the methods of triaxial mechanical testing (inflation, extension and twist), in situ microstructure imaging, image processing and reconstruction, and developed a novel predictive micromechanics model of the adventitia. Here, we propose to extend these developments to the entire wall to provide a validated virtual vessel model that can be used to verify various hypotheses quantitatively (e.g., role of hypertension on IH). The success of the proposed microstructure-based computational framework will provide an accurate and reliable mathematical description of the structure-function relation of coronary arteries, and result in a new level of understanding for the mechanical response of the vessels. Furthermore, the extensive quantitative experimental data of the microstructures in health and hypertension (including IH) and their deformation will greatly enrich the understanding of the mechanical environment of the fibers and SMC and the remodeling process in atherogenesis.