Type I Collagen Biomechanics in Aging Vasculature

细胞外基质和细胞骨架：动脉僵硬增加是心血管发病率和死亡率的主要危险因素。与年龄相关的血管和心脏硬度的增加伴随着胶原表达和结构的改变，这种关系是否是因果关系尚不清楚。I型胶原是心血管组织的主要成分，通常是异三聚体，两个α1(I)链和一个α2(I)链[α1(I)2α2(I)]。然而，在OIM小鼠中，I型胶原仅由alpha1(I)同源三聚体alpha1(I)3(alpha2(I)基因零突变的结果)组成。OIM鼠标为研究Alpha2(I)链的功能必要性提供了一个极好的模型。我们推测，α2(I)链的缺失严重扰乱了胶原纤维的组织和/或分子间的交联，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这一假说，显示OIM小鼠的主动脉僵硬和断裂强度显著降低。这项先导性研究将开始解决这样一个问题：随着年龄的增长，OIM主动脉弹性的增加(硬度的降低)是否会起到保护作用，或者其断裂强度的降低是否会有害：缺乏α2(I)胶原蛋白是否会使OIM小鼠容易发生病理性心血管并发症？具体地说，我们将测定生物力学特性(断裂强度和弹性)，定量胶原和胶原交联物，并通过超声和组织学评估OIM和野生型小鼠3个月和18个月的主动脉。尽管胶原结构的改变无疑有助于衰老的生理学和心血管疾病的病理生理学，但目前尚不清楚胶原蛋白和衰老在疾病的发生、发展和临床结局中的作用。这项研究的主要成果将是开始确定α2(I)胶原在衰老过程中在血管生物力学和僵硬中的结构/功能作用，并确定一个潜在的小鼠模型，用于评估动脉僵硬在衰老和心血管功能中的机制和发病机制。通过我们的多学科方法，我们独一无二地准备在衰老的背景下研究I型胶原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.