A Validated Micro-Structural Mechanical Model of Coronary Arteries

描述(由申请人提供)：机械应力和应变在血管细胞生物学和病理学中的重要性得到了很好的认识。血管生理学和病理生理学中的许多问题都依赖于血管壁细胞和细胞外基质中的应力和应变。可以测量应变，但不能测量应力。应力的确定需要对组织的力学性质有一个精确的了解；即，我们必须知道不同层血管壁的本构方程。这项建议的目的是开发和实验验证猪冠状动脉外膜的微观结构模型。该方案包括多光子显微镜(MPM)，它能够识别机械载荷下冠状动脉外膜的弹性蛋白和胶原纤维，以及利用现代计算能力来处理复杂的微结构几何和边界条件的数值方法。其具体目的是：1)使用MPM对冠状动脉外膜中胶原和弹性蛋白纤维在同时加载条件下的三维微观结构进行量化；2)基于Aim 1中的微观结构数据建立本构模型，并使用直接有限元(FE)模拟进行力学测试；3)在正常和高血压外膜测量的双轴条件下，利用载荷-变形关系对Aim 2的本构模型进行实验验证。这一建议的主要贡献有三个方面：第一，计算框架将提供冠状动脉结构-功能关系的数学描述，并导致对血管机械响应的理解达到新的水平。第二，对健康人和高血压人的显微结构及其变形的大量实验数据将丰富对纤维和成纤维细胞的力学环境的了解。第三，建议的计算框架的直接应用将澄清心血管研究中的几个重要假设，例如高血压患者冠状动脉僵硬增加的微观结构基础。公共卫生相关性：冠状动脉疾病仍然是美国和世界各地发病率和死亡率的主要原因，特别是在高血压患者中。毫无疑问，机械应力和应变在血管健康和疾病中起着重要作用。这一建议的主要贡献是提供了健康和高血压患者冠状动脉结构-功能关系的数学描述，并导致了对血管机械反应的新的理解水平。

DESCRIPTION (provided by applicant): The significance of mechanical stresses and strains in vascular cell biology and pathology are well recognized. A large number of problems in vascular physiology and patho- physiology depend on the stresses and strains in the cellular and extracellular matrix of the vessel wall. It is possible to measure the strains but not the stresses. The determination of the stresses requires a precise understanding of the mechanical properties of the tissue; i.e., we must know the constitutive equations for the different layers of the vessel wall. The objective of this proposal is to develop and experimentally validate a microstructural model of the adventitia of swine coronary arteries. The proposal involves Multi-Photon Microscopy (MPM) that enables the identification of elastin and collagen fibers of the coronary arterial adventitia under mechanical loading, and numerical methods that take advantage of modern computational capability to deal with the complex microstructural geometry and boundary conditions. The Specific Aims are: 1) To quantify the 3-D microstructure of collagen and elastin fibers in coronary arterial adventitia using MPM under simultaneous loading conditions; 2) To develop a constitutive model based on the microstructural data in Aim 1 and to perform mechanical test with direct finite element (FE) simulations; and 3) To experimentally validate the constitutive model of Aim 2 with load-deformation relation under biaxial conditions for fibers and cells measured in normal and hypertensive adventitia. The major contributions of this proposal are three fold: First, the computational framework will provide a mathematical description of the structure-function relation of coronary arteries, and result in a new level of understanding of the mechanical response of the blood vessel. Second, the extensive experimental data of the microstructures in health and hypertension and their deformation will enrich the understanding of the mechanical environment of the fibers and fibroblasts. Third, the direct application of the proposed computational framework will clarify several important hypotheses in cardiovascular research, such as the microstructural basis of the increased stiffness of coronary arteries in hypertension. PUBLIC HEALTH RELEVANCE: Coronary artery disease remains a major cause of morbidity and mortality in the U.S. and around the world especially in patients with hypertension. There is no doubt that mechanical stresses and strains play an important role in vessel health and disease. The major contributions of this proposal is to provide a mathematical description of the structure-function relation of coronary arteries in health and hypertension, and result in a new level of understanding of the mechanical response of the blood vessel.