Sex- and Race-Based Differences in the Effects of Acute and Chronic Exercise on Vascular Function and Circulating MicroRNA

Abstract

Cardiovascular disease (CVD) is the leading global cause of death. Disparities in CVD development exist, with greater rates observed in men than women and in African Americans (AA) than Caucasian Americans (CA). It is crucial to determine the molecular mechanisms underlying these disparities in order to formulate preventative strategies. Regular aerobic exercise reduces CVD risk, while acute exercise is a useful stimulus to reveal impairments in cardiovascular function not apparent at rest. This dissertation utilizes approaches to identify sex- and race-based differences in vascular function within young, healthy individuals, indicative of future CVD risk, including the use of acute exercise as a cardiovascular stimulus and the exercise-trained individual as a model of superior cardiovascular health. Aim #1 shows that exercise training is associated with beneficial effects of the circulating factors in serum on vascular endothelial cells, in a sex-specific manner, suggesting that circulating factors are differently affected by exercise training in men and women. Aim #2 shows that endothelial function and central arterial stiffness respond similarly to acute exercise in AA and CA. Carotid arterial compliance, however, is increased only in CA during exercise recovery. MicroRNAs (miRs) are epigenetic modulators of gene expression implicated in CVD development. Blood-borne circulating miRs (ci-miRs) are paracrine/endocrine molecules and preclinical biomarkers, yet sex- and race-based differences in ci-miRs are understudied. Additionally, ci-miRs are altered with exercise and may mediate training-induced vascular adaptations. Aim #3 of this dissertation reveals that the resting concentrations of select vascular-related ci-miRs differ based on sex and exercise training status, but not race. In response to acute exercise however, several anti-inflammatory ci-miRs increased significantly in CA, but not AA. Additionally, the changes in one anti-inflammatory ci-miR exhibited race-specific correlations with the changes in carotid arterial compliance identified in Aim #2. Aim #4 investigates the hypothesis that exercise elicits endothelial integral damage, and that this may mediate changes in vascular function and endothelial-derived ci-miRs. By measuring different endothelial-derived circulating factors, we show that exercise likely does not cause endothelial cell detachment or apoptosis. Thus, ci-miR are likely released via a selective method of secretion, rather than passively leaking from damaged endothelium.