Multi-Scale Integration of Extracellular Matrix Mechanics in Vascular Remodeling

项目摘要 大弹性动脉的硬度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， 非糖尿病患者。生物力学和生物化学变化与血管重塑有关 在糖尿病患者中。作为一种长寿命的细胞外基质（ECM）蛋白，弹性蛋白提供了必要的弹性 动脉壁的周期性变形。生物化学暴露的累积效应在 老化和疾病会极大地损害其机械功能。然而，人们对它知之甚少。 耦合的生化和机械变化对心血管系统的重要病理生理作用 系统这种缺乏理解很可能与ECM机制研究不足有关， 缺乏实验技术来揭示结构，机械和生物化学之间的相互作用， 动脉重塑中的ECM成分。弹性蛋白和胶原蛋白是大弹力纤维中的主要ECM成分。 动脉弹性蛋白和胶原蛋白之间的结构和机械生物学相互作用，主要负荷- 动脉壁中的轴承组件对于动脉的正常功能是重要的。然而，在所有以前的 在动脉的结构模型中，ECM成分之间的相互作用通常被忽略。 这项工作的总体目标是开发一个多尺度的ECM力学模型， 修饰和ECM相互作用，并使用此模型来研究生物化学，结构和机械 在来自患有糖尿病的人和小鼠的大弹性动脉中重塑动脉ECM，具有两个特定目的： 具体目标1：创建ECM力学的多尺度结构-化学-力学模型， ECM成分之间内在的机械、结构和生物化学相互作用;和特定目的2： 使用该模型研究糖尿病ECM的多尺度机械、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，可能会导致一个重大的 基于结构的本构建模的进展。ECM的生物化学修饰代表了一种 在老化过程中的软生物组织的本构建模领域中的一个重要新兴领域， 疾病建议的工作使用结构确定性的方法，将纤维网络 结构，先进的成像技术和严格的机械测试，使开发多功能 ECM力学和相互作用的比例模型。结合糖尿病研究，本研究方法 具有很大的潜力，以解开ECM重塑的潜在关键机制。由于重要的 细胞和ECM之间的相互作用，着眼于ECM可能会开辟新的视角， 治疗干预。本研究的结果将为我们对这一现象的研究提供新的认识。 糖尿病血管并发症的机制，并有可能导致范式转变， 为糖尿病患者开发预防和治疗药物。 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