Date of Award
Doctor of Philosophy (PhD)
Large elastic arteries are a composite structure composed of cells and extracellular matrix proteins. Passive arterial mechanical behavior is determined by the composition of extracellular matrix proteins, in particular elastin and collagen. Elastin provides reversible elasticity to the large elastic arteries during cyclic loading and dampens the pulsatile flow from the left ventricle, reducing the workload on the heart and protecting the end organs. Disorganization and insufficiency of elastin alters the passive mechanical behavior of the large arteries. The arterial wall responds to changes in elastin organization or amount through matrix remodeling. Aging causes elastin fragmentation and degradation which changes the elastin:collagen protein ratio and increases the arterial stiffness. More pressure is required to distend the arterial wall to maintain normal function, so a pathological adaptation results in hypertension. While progress has been made in understanding the relationship between arterial stiffness and hypertension, it remains unclear how elastin amounts affect matrix remodeling and how sex differences play a role in vascular aging. Understanding the contribution of different wall components to mechanical behavior and matrix remodeling in males and females is useful for identifying factors that may lead to and predict related cardiovascular risk with aging.
The goal of this dissertation is to elucidate mechanisms leading to arterial stiffening through matrix remodeling in the context of aging. Two aims of this study are (1) to evaluate how variations in elastin amount contribute to the arterial mechanics of male and female mice during aging; and (2) to use a mathematical model to investigate the mechanical contribution of matrix proteins to the sex-specific physiological arterial stiffness and elastic energy storage during aging. We collected arterial mechanical and physiological data from elastin wild-type Eln+/+ and heterozygous Eln+/- male and female mice to determine the relationship between the mechanical properties of arteries and cardiac function at different ages. Our results demonstrate a relationship between sex-specific increases in arterial stiffness and pulse pressure. We highlight the importance of maintaining circumferential mechanical properties including stretch, stress, and stiffness during aging, despite differences in sex and genotype. We suggest that a reduction in elastic energy storage leads to an increase in heart weight despite conservation of biaxial stiffness. These observations provide insight into sex-related mechanical changes in the arterial wall through matrix remodeling during the aging process, establishing a strong link between arterial mechanics and cardiac function. Further work may include quantifying changes in cell mechanics and hormonal effects on the cardiovascular system during the aging process.
Spencer Lake, Robert Mecham, Ruth Okamoto, Amit Pathak,