The proposed project will examine the effects of menopause on the cardiovascular system. Endothelial cells play a pivotal role in controlling the cardiovascular system by production of a variety of vasoactive substances that effect vasoconstriction, including endothelin-1 (ET-1), and vasodilation, including nitric oxide (NO). Both the ET-1 and NO systems show age-related changes and are influenced by sex hormones, suggesting that the two systems can be altered by estrogen deficiency after menopause. The general hypothesis to be tested is that reproductive system aging in women, specifically menopause, alters vascular control mechanisms of the endothelium resulting in attenuated vasodilator and exaggerated vasoconstrictor influences on blood vessels. These alterations predispose postmenopausal women to cardiovascular diseases. Long-term objectives are: (a) to define the paracrine and autocrine control mechanisms of the vascular endothelium that are altered by menopause and (b) to establish rationale for preventative and/or therapeutic interventions. Specific aims are: 1: To define menopause-related alterations in mechanisms of endothelium-mediated vasodilation by the NO system. 2: To define menopause-related alterations in mechanisms of endothelium- mediated vasoconstriction by the ET-1 system. Studies will be done in post-menopausal women without hormone replacement and premenopausal women ages 45-55 to examine whether vasodilator effects of the endothelial NO decrease after menopause and vasoconstrictor effects of ET-1 increase after menopause. Studies will use in vivo intradermal microdialysis combined with blood flow measurements by laser-Doppler flowmetry.