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.
| Wenstrup, Richard J; Florer, Jane B; Davidson, Jeffrey M et al. (2006) Murine model of the Ehlers-Danlos syndrome. col5a1 haploinsufficiency disrupts collagen fibril assembly at multiple stages. J Biol Chem 281:12888-95 |
| Pfeiffer, Brent J; Franklin, Craig L; Hsieh, Fu-hung et al. (2005) Alpha 2(I) collagen deficient oim mice have altered biomechanical integrity, collagen content, and collagen crosslinking of their thoracic aorta. Matrix Biol 24:451-8 |
