Sex differences in vascular dysfunction in early diabetes
Mitchell, Adam Richard.
Thesis (Ph.D.)--Georgetown University, 2009.; Includes bibliographical references.; Text (Electronic thesis) in PDF format. Diabetes is a significant cause of morbidity and mortality, and is known to increase vascular dysfunction and the development of cardiovascular disease (CVD) in humans. In addition, sex differences have been found in the development and/or progression of both diabetes and CVD, although the mechanisms underlying specific sex differences in vascular function are not well understood. The objective of the present work was to investigate potential sex differences in mesenteric arteriolar responses to adrenergic vasoconstriction and endothelium-dependent vasodilation in normal and diabetic rats, and assess the role of nitric oxide (NO) production in modulating these responses. Our results indicate that vessels from normal female rats were 26% (P<0.05) more sensitive to the constrictor effects of the adrenergic drug phenylephrine (PE), despite having a higher PE-stimulated production of NO, than vessels from normal male rats. There was no difference in acetylcholine (Ach)-induced vasorelaxation between the sexes, and the findings indicate that both NO- and endothelium derived hyperpolarizing factor (EDHF)-mediated vasodilations are equivalent between the sexes. Induction of diabetes had sex-specific effects on responses of mesenteric vessels. In streptozotocin induced diabetes, only vessels from females had an increased sensitivity to phenylephrine compared to non-diabetic animals. When GH was added to the model (to better mimic human diabetes), the increased sensitivity to adrenergic vasoconstriction was lost in females, but not males; in males (but not females) NO production during adrenergic vasoconstriction was increased. Thus, a complex picture emerges, whereby vascular control appears differentially affected by diabetes between sexes. We hypothesize that changes in NO modulation of vasoconstriction in diabetes may be particularly significant, and might relate to the loss of CV protection occurring in diabetic females. We suggest that changes in vasoconstrictor responses to catecholamines, along with alterations in the endothelial NO system are important contributors to vascular dysfunction and gender differences associated with diabetes.
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