Type I Collagen Biomechanics in Aging Vasculature

细胞外基质和细胞骨架：动脉硬化增加是心血管发病率和死亡率的主要危险因素。年龄相关的血管和心脏硬度增加伴随着胶原表达和结构的改变，这种关系是否有因果关系尚不清楚。I型胶原是心血管组织的主要成分，通常是异三聚体，有两条alpha1(I)链和一条alpha2(I)链，[alpha1(I)2alpha2(I)]。然而，在oim小鼠中，I型胶原蛋白完全由alpha1(I)三聚体，alpha1(I)3 （alpha2(I)基因零突变的结果）组成。oim小鼠为研究alpha2(I)链的功能必要性提供了一个极好的模型。我们推测，α 2(I)链的缺失严重扰乱了胶原纤维组织和/或分子间交联，损害了心血管组织的结构完整性。初步的生物力学测量支持了这一假设，揭示了oim小鼠主动脉硬度和断裂强度的显著降低。这项初步研究将开始解决以下问题：随着年龄的增长，主动脉弹性的增加（刚度的降低）是具有保护作用还是其断裂强度的降低是有害的：α 2(I)胶原蛋白的缺乏是否会使小鼠易患病理性心血管并发症？具体来说，我们将测定3月龄和18月龄野生型小鼠主动脉的生物力学特性（断裂强度和弹性），定量胶原蛋白和胶原交联，并通过超声和组织学评估。虽然胶原结构的改变无疑有助于衰老的生理和心血管疾病的病理生理，但胶原和衰老在疾病发生、进展和临床结果中的作用目前尚不清楚。本研究的主要结果将是开始确定衰老过程中α 2(I)胶原蛋白在血管生物力学和刚度中的结构/功能作用，并确定一种潜在的小鼠模型，用于评估衰老和心血管功能中动脉刚度的机制和发病机制。通过我们的多学科方法，我们独特地准备在衰老背景下研究I型胶原蛋白和血管生物力学之间的联系。

Extracellular Matrix and Cytoskeleton: Increased arterial stiffness is a major risk factor for cardiovascular morbidity and mortality. Age associated increases in vascular and cardiac stiffness are accompanied by altered collagen expression and structure, and whether this relationship is causal is unknown. Type I collagen, a major component of cardiovascular tissue, is normally heterotrimeric, two alpha1 (I) chains and one alpha2(I) chain, [alpha1(I)2alpha2(I)]. However, in oim mice, type I collagen is exclusively composed of alpha1(I) homotrimers, alpha1(I)3, (result of a null mutation in the alpha2(I) gene). The oim mouse offers a superb model for examining the functional necessity of the alpha2(I) chain. We postulate that the absence of alpha2(I) chains seriously perturbs collagen fibrillar organization and/or intermolecular crosslinking, compromising the structural integrity of cardiovascular tissue. Preliminary biomechanical measurements support this hypothesis, revealing substantial reductions in aortic stiffness and breaking strength in oim mice. This pilot study will begin to address the query: With increasing age will the increased elasticity (decreased stiffness) of the oim aorta be protective or will its decreased breaking strength be detrimental: will the absence of alpha2(I) collagen predispose oim mice to pathological cardiovascular complications? Specifically, we will determine the biomechanical properties (breaking strength and elasticity), quantitate collagen and collagen crosslinks, and evaluate by ultrasonography and histology oim and wildtype mice aortas at 3 and 18 months of age. Although alterations in collagen structure are unquestionably contributory to the physiology of aging and pathophysiology of cardiovascular disease, the role of collagen and aging in disease development, progression, and clinical outcome are presently unknown. Major outcomes of this study will be to begin defining the structural/functional role of alpha2(I) collagen during aging in vascular biomechanics and stiffness, and to identify a potential mouse model for evaluating the mechanisms and pathogenesis of arterial stiffness in aging and cardiovascular function. With our multidisciplinary approach, we arc uniquely poised to study the link between type I collagen and vascular biomechanics in the context of aging.