The purpose of this R01 proposal is to determine the key functional mechanisms by which the loss of female sex hormones, particularly estradiol (E2), contribute to the age-related decrease in large artery compliance. The overall hypothesis is that basal large artery compliance will decrease in response to acute sex hormone suppression in pre- and perimenopausal women due in part to a decrease in vascular endothelial-dependent vasodilatory tone mediated, in part, to the development of vascular oxidative stress. However, E2 administration during sex hormone suppression will decrease vascular oxidative stress, improve endothelial vasodilatory tone and restore arterial compliance to basal levels. Secondary and tertiary hypotheses are that the changes in arterial compliance and vasodilatory function with sex hormone suppression and E2 will be related to unfavorable, and favorable, respectively, changes in vascular endothelial cell protein expression including oxidant (e.g., NADPH) and antioxidant (e.g., glutathione peroxidase) enzymes, vasoconstrictors (endothelin- 1), and estrogen receptor alpha (ERalpha). To test these hypotheses, healthy pre-, peri-, and postmenopausal women will be studied at before and following acute sex hormone suppression (gonadotropin releasing hormone antagonist [GnRHant]) with or without E2 add-back therapy. The GnRHant intervention will enable us to study the direct mechanisms associated with sex hormone deficiency and the E2 add-back intervention will enable us to isolate the independent effects of E2. Insight into the molecular mechanisms mediating the decrease in large artery compliance will be obtained using a novel translational research technique to determine changes in vascular endothelial cell protein expression of genes involved in the regulation of cellular and systemic adaptations to aging and sex hormone deficiency including oxidative stress, nitric oxide bioavailability, and the potent transcription factor ERalpha proteins. The results should provide new insight into the integrative biological mechanisms by which sex hormone deficiency modulates the age-related reduction in large artery compliance in women as they transition through the menopause.
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