Multi-Scale Integration of Extracellular Matrix Mechanics in Vascular Remodeling

项目摘要 大弹性动脉的僵硬增加是心血管疾病进展的重要因素 疾病。糖尿病患者在相对年轻的年龄表现出加速的大动脉硬化。 非糖尿病受试者。生物力学和生化变化与血管重塑有关 在糖尿病患者中。作为一种长寿的细胞外基质(ECM)蛋白，弹性蛋白提供必要的弹性 用于动脉壁的周期性变形。在此期间遇到的生化暴露的累积影响 衰老和疾病会极大地损害其机械功能。然而，人们对此知之甚少 生化与机械耦合变化对心血管的重要病理生理作用 系统。这种缺乏理解很可能与未被充分研究的ECM机制和 缺乏揭示结构、机械和生物化学相互作用的实验技术 血管重塑中的细胞外基质成分。弹性蛋白和胶原是大弹性中的主要ECM成分 动脉。弹性蛋白和胶原之间的结构和力学生物相互作用，主要负荷- 动脉壁中的承重成分对正常运作的动脉非常重要。然而，在所有以前的 动脉的结构模型、细胞外基质成分之间的相互作用通常被忽略。 这项拟议工作的总体目标是开发一个多尺度的ECM机制模型，该模型可以是生化的 修饰和ECM相互作用，并使用该模型来研究生化、结构和力学 人和糖尿病小鼠大弹性动脉ECM的重塑有两个特定的目的： 具体目标1：创建ECM力学的多尺度结构-化学-机械模型，将 ECM成分之间的内在机械、结构和生物化学相互作用；和具体目标2： 利用该模型研究糖尿病患者ECM的多尺度力学、结构和生化重塑。 考虑弹性蛋白和胶原蛋白之间的相互作用是一个创新的想法，并可能导致一个主要的 基于结构的本构模型研究进展。细胞外基质的生化修饰代表着一种 生物软组织老化本构模型研究领域的重要新兴领域 疾病。拟议的工作使用结构决定论方法来结合纤维网络 结构、先进的成像技术和严格的机械测试使开发一种多 ECM力学和相互作用的比例模型。结合对糖尿病的一项研究，这种研究方法 有很大的潜力来揭示ECM重塑的潜在关键机制。由于重要的是 细胞和细胞外基质之间的相互作用，观察细胞外基质可能会打开新的视角 治疗性干预。这项研究的结果将为我们对潜在的 糖尿病血管并发症的机制，并有可能导致范式的转变 开发糖尿病患者的预防和治疗方法。 1

PROJECT ABSTRACT Increased stiffness in large elastic arteries is a significant contributor to the progression of cardiovascular disease. Diabetic patients show accelerated large arterial stiffening at a relatively young age compared to nondiabetic subjects. Biomechanical and biochemical changes have been associated with vascular remodeling in diabetic patients. As a long-lived extracellular matrix (ECM) protein, elastin provides the elasticity necessary for cyclic deformation of the arterial wall. The cumulative effects of biochemical exposure encountered during aging and disease can greatly compromises its mechanical function. However little is known about the important pathophysiological effects of the coupled biochemical and mechanical changes on the cardiovascular system. This lack of understanding is most likely to be correlated with the understudied ECM mechanics and the lack of experimental techniques to reveal the structural, mechanical, and biochemical interactions among ECM constituents in arterial remodeling. Elastin and collagen are the major ECM constituents in large elastic arteries. The structural and mechanobiological interactions between elastin and collagen, the primary load- bearing components in the arterial wall, are important for properly functioning arteries. However in all previous structural models of arteries, interactions among ECM constituents are usually ignored. The overall goal of this proposed work is to develop a multi-scale model of ECM mechanics that biochemical modifications and ECM interactions, and use this model to study the biochemical, structural, and mechanical remodeling of arterial ECM in large elastic arteries from humans and mice with diabetes with two specific aims: Specific aim 1: Create a multi-scale structural-chemo-mechanical model of ECM mechanics that integrate the intrinsic mechanical, structural, and biochemical interactions among ECM constituents; and Specific Aim 2: Use the model to study the multi-scale mechanical, structural, and biochemical remodeling of ECM in diabetes. Consideration of the interactions between elastin and collagen is an innovative idea and may lead to a major advancement in structure-based constitutive modeling. Biochemical modifications of ECM represent an important emerging area in the field of constitutive modeling of soft biological tissues in aging and many diseases. The proposed work using a structural deterministic approach to incorporate fibrous network structure, advanced imaging technique, and rigorous mechanical testing made it possible to develop a multi- scale model of ECM mechanics and interactions. Combining with a study in diabetes, this research approach has a great potential to unravel the underlying key mechanisms of ECM remodeling. Due to the important reciprocal interactions between cells and ECM, looking at the ECM may open up new perspectives in therapeutic interventions. Results form this study will provide new understandings on the underlying mechanisms of vascular complications in diabetes, and have the potential to lead to a paradigm shift in developing prevention and therapeutics for diabetic patients. 1