Multiscale Effects of Aging on Elastic Arterial Tissue Mechanics

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Project Summary Elastin evolved in vertebrates to support a closed, pulsatile circulatory system, and was subsequently co-opted to support reversible extension in a variety of organs, such as the lungs, viscera, and skin. It has remarkable elastic properties supporting recoil following large strains with minimal loss of energy over millions to billions of stretch-recoil cycles without failure. Despite its important biological and mechanical function, the structure of the entire elastin precursor monomer (tropoelastin) and the resulting polymer has been unknown, hampering full molecular understanding of elastin function in both health and disease. Our prior research has determined the shape of tropoelastin using molecular modeling of the entire polypeptide chain, showing a matching overall shape to small-angle X-ray scattering data, and achieved atomic resolution of the structure. We showed that the model correctly identified structural changes associated with mutations in key molecular sites and discovered their mechanisms of impact, linking structure to function. Furthermore, we showed that the elastic fiber network stiffens progressively with non-enzymatic glycation. The overall goal of this proposal is to leverage these groundbreaking preliminary results to understand the structural and molecular determinants of elastin function in arterial tissue in health and upon aging, using an interdisciplinary experimental-modeling approach, employing molecular and multiscale modeling, biochemical characterization, multiscale biomechanical testing, and optical imaging within three research aims: (1) identify putative aging-associated damage sites and establish coupling mechanisms between processes driving mechanical changes in elastin dimers, the smallest representative molecular unit of native enzymatically crosslinked elastin; (2) determine the role of native enzymatic and non-enzymatic (aging-linked pathological) crosslinks in modulating elastic fiber mechanics via a mesoscale model of elastic fibers; and (3) resolve how fiber mechanics and the propensity of crosslinking at the microscale impact elastic fiber network architecture and mechanics during aging. The proposed research will establish a framework to broadly investigate the multiscale structure and multifactorial modifications associated with aging and age-related diseases that affect structural change and mechanical function in elastic tissue. Insights gained through these studies will have a translational impact on the development of preventative, diagnostic and reparative interventions to cardiovascular and other age-related diseases. 1