ROLE OF NO AND ESTRADIOL IN AGING AND ATHEROGENESIS

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During aging in women, two important changes occur which affect the vascular system. The first is menopause which is associated with estrogen withdrawal and the other is endothelial dysfunction manifested by a decrease in endothelium dependent vasodilation, possibly a reflection of a decrease in NO production by endothelial cells. These two changes may be independent of each other or may be interlinked. We and others have demonstrated that estradiol (E2) increases NO production. Therefore, endothelial dysfunction seen during aging and menopause as manifested by a decrease in endothelium dependent vasodilation and decrease in NO production may be explained just on the basis of E2 withdrawal alone. Estrogen replacement to postmenopausal women has been utilized for potential benefits related to the cardiovascular system. However, the precise mechanism(s) by which estrogens exert a beneficial effect on the cardiovascular system is not known. On the other hand, a recent study indicates that administration of a combination of estrogen and a progestin to women with well-documented coronary artery disease was associated with an increase in the incidence of a second coronary event in the first year of the study compared to the placebo group. In this study, there was no group in which women received E2 alone. Therefore, the role of E2 in modulating atherogenesis, once the disease is established is not known. Similarly, post-menopausal women are occasionally administered testosterone (t) to increase their sexual function but the effect of T on atherogenesis is not known. The overall hypothesis to be tested is that "the mere withdrawal of E2 or T leads to a decrease in NO synthesis, and thereby, to a pro-inflammatory response of the vascular wall leading to changes seen early in atherogenesis. A corollary could be that the atherogenic process on the extreme might increase the production of OONO and under such conditions NO inhibition might actually be beneficial." We propose to mimic the postmenopausal state in experimental animals by ovariectomy (OVX). We propose to mimic endothelial dysfunction by pharmacological means by administering animals an inhibitor of NO synthesis. The hypothesis will be tested under three specific aims.