Deer, Rachel Renee (2013-07). Physiological Factors that Modulate Vascular Function: States of Endothelial Dysfunction and Therapeutic Interventions. Doctoral Dissertation.
Thesis
This dissertation investigated the role of two therapeutic interventions (exercise training and hormone replacement therapy) on two different states of endothelial dysfunction, chronic coronary occlusion and aging. Despite remarkable evidence for the therapeutic benefits of physical activity, the mechanisms by which regular exercise improves vascular function in the setting of coronary artery disease are not fully understood. Similarly, the effects of aging and hormone replacement therapy on vascular function are often paradoxical and poorly understood. Thus, the first project utilized a model of chronic coronary artery occlusion to evaluate the effects of exercise training on cellular and molecular adaptations of collateral-dependent coronary vasculature compared to the nonoccluded control. This study provided new evidence that exercise training concomitantly enhanced the contributions of multiple vasodilator mechanisms, including nitric oxide, prostacyclin and BKCa channels to vascular function in the ischemic heart. Increased contribution of multiple vasodilator signaling pathways after exercise training appears to promote compensation or redundancy to ensure adequate vasodilation and coronary vascular blood flow. The second project utilized a model of aging to evaluate the interactive effects of age and hormone replacement therapy on the cellular and molecular mechanisms underlying the regulation of cerebrovascular function. Although the mechanisms underlying the beneficial effects of estrogen on cerebrovascular function have been studied at length, the mechanisms responsible for age-dependent deleterious effects of estrogen are largely unknown. The results of this study revealed that estrogen exerts divergent effects on the cerebrovasculature with advancing age. In younger females, estrogen replacement treatment is beneficial, attenuating vasoconstriction primarily by the COX-1 dependent prostanoid pathway and increased PGI2 production. In contrast, in older reproductively senescent females, estrogen augmented vasoconstriction via the COX-2 dependent prostanoid pathway and increased TXA2 production. A better understanding the mechanisms by which estrogen exerts beneficial versus detrimental effects on the cerebrovasculature may lead to new gender-specific therapeutic agents designed specifically to target the cerebrovascular system and other estrogen-responsive tissues.
