Type I Collagen Biomechanics in Aging Vasculature

老化脉管系统中的 I 型胶原生物力学

• 批准号: 6333628
• 负责人: CHARLOTTE L PHILLIPS
• 金额: $ 7.25万
• 依托单位: UNIVERSITY OF MISSOURI-COLUMBIA
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-06-01 至 2003-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6333628
• 关键词: aging; angiocardioultrasonography; aorta; biomechanics; collagen; elastin; gene induction /repression; gene mutation; laboratory mouse; osteogenesis imperfecta; protein structure function; proteoglycan; vascular resistance; vascular smooth muscle; ventricular hypertrophy

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.

细胞外基质和细胞骨架：动脉僵硬度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僵硬度增加伴随着胶原蛋白表达和结构的改变，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，通常是异源三聚体，两条α 1（I）链和一条α 2（I）链，[α 1（I）2 α 2（I）]。然而，在oim小鼠中，I型胶原仅由α 1（I）同源三聚体，α 1（I）3组成（α 2（I）基因无效突变的结果）。oim小鼠为研究alpha 2（I）链的功能必要性提供了极好的模型。我们推测，α 2（I）链的缺乏严重扰乱胶原纤维组织和/或分子间交联，损害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设，显示oim小鼠的主动脉硬度和断裂强度显著降低。该初步研究将开始以解决以下问题：随着年龄的增长，主动脉弹性增加（刚度降低）是否具有保护作用，或其断裂强度降低是否有害：缺乏α 2（I）胶原蛋白是否会使小鼠易患病理性心血管并发症？具体来说，我们将确定生物力学性能（断裂强度和弹性），定量胶原和胶原交联，并通过超声检查和组织学评估3月龄和18月龄的野生型小鼠椎间盘。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，但胶原和衰老在疾病发展、进展和临床结局中的作用目前尚不清楚。本研究的主要结果将是开始定义老化过程中α 2（I）胶原在血管生物力学和僵硬度中的结构/功能作用，并确定一种潜在的小鼠模型，用于评估老化和心血管功能中动脉僵硬度的机制和发病机制。通过我们的多学科方法，我们独特地准备研究衰老背景下I型胶原蛋白和血管生物力学之间的联系。