Elucidation of novel therapeutic targets in the microvasculature of hypertensive humans
Open Access
- Author:
- Craighead, Daniel Harrison
- Graduate Program:
- Kinesiology
- Degree:
- Doctor of Philosophy
- Document Type:
- Dissertation
- Date of Defense:
- February 24, 2017
- Committee Members:
- Lacy M. Alexander, Dissertation Advisor/Co-Advisor
W. Larry Kenney, Committee Chair/Co-Chair
Sara B. Ferguson, Committee Member
Timothy R. McConnell, Committee Member
Kelly J. Karpa, Outside Member - Keywords:
- cutaneous
microvasculature
endothelium
menthol
hypertension
lysyl oxidase - Abstract:
- The cutaneous microvasculature is an accessible microvascular bed that has utility for examining mechanisms of systemic microvascular dysfunction. Hypertension is a widespread chronic disease associated with microvascular dysfunction and pathological vessel remodeling. Therefore, comprehensive treatment of hypertension requires interventions that improve microvascular function and structure. The purpose of this series of studies was to examine the effects of different candidate therapeutic targets and treatments for hypertension in the cutaneous microvasculature. In the first study, I found that menthol, a selective TRPM8 channel agonist, induced cutaneous vasodilation through endothelium- and sensory-nerve dependent mechanisms. Importantly, menthol-induced vasodilation was not attenuated in essential hypertensive men and women, suggesting that the vasodilatory response to menthol is preserved. In the second study, I found that acute inhibition of lysyl oxidase, an enzyme regulating collagen cross-linking and vascular stiffness, augments smooth muscle-dependent vasodilation and vasoconstriction in normotensive, but not hypertensive, men and women. In the final study, I examined endothelium-dependent vasodilation and maximal vasodilator capacity in normotensive, unmedicated hypertensive, and medicated hypertensive subjects whose blood pressure was controlled through antihypertensive pharmacotherapy. I found that endothelial function is attenuated in hypertensive subjects, but is improved when blood pressure is normalized with pharmacotherapy. However, maximal vasodilatory capacity was attenuated in unmedicated and medicated hypertensive subjects, demonstrating that structural decrements persisted with pharmacotherapy. Together these studies helped evaluate candidate therapies to improve microvascular structure and function in men and women with essential hypertension.