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是公认的。本提案的目的是开发健康和高血压患者冠状动脉整个血管壁的经验证的微观结构模型（作为内膜增生的机械刺激，IH）。该提案涉及原位多光子显微镜（MPM），使弹性蛋白，胶原蛋白和平滑肌细胞（SMC）的冠状动脉在机械负荷下的三维描绘，实验方法来量化壁的分层结构，数值算法，利用非线性力学和现代计算能力来处理复杂的微观结构几何形状和边界条件。 因此，本论文的具体目标是：1）建立基于超微结构（纤维和SMC）的冠状动脉壁被动和主动本构模型; 2）验证目标1中的动脉壁全本构模型 使用被动和主动的（宏观）三轴力学试验和原位成像的微观结构变形的数据;和3）阐明高血压对IH的力学作用，使用Aim 2的验证模型结合有限元分析和实验验证。我们以前已经建立了三轴力学测试（膨胀，伸展和扭曲），原位显微结构成像，图像处理和重建的方法，并开发了一种新的预测外膜的微观力学模型。在这里，我们建议将这些开发扩展到整个血管壁，以提供经验证的虚拟血管模型，该模型可用于定量验证各种假设（例如，高血压对IH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，并导致对血管的机械响应的新水平的理解。此外，健康和高血压（包括IH）的微观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.