SEX HORMONES AND CORONARY ARTERY REACTIVITY

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The age adjusted incidence of coronary artery disease of premenopausal women lags approximately ten years behind that of men. After menopause, the incidence rises at a rate similar to that of men. This suggests a hormone, possibly estrogen protects the coronary arteries and heart by unknown mechanisms. In preliminary study, we have shown diminished contraction to thromboxane of coronary artery rings prepared from female guinea pigs compared to males after the inhibition of guanylate cyclase. Further, equal concentrations of cGMP produce greater relaxation of thromboxane-contracted coronary arteries from females compared to males. These findings suggest a sexual dimorphism in cGMP synthesis/breakdown. Nitric oxide (NO), an autacoid with diverse roles works by activating cGMP. NO stimulates endothelial but inhibits smooth muscle cell proliferation. We have shown that estradiol increases the activity of nitric oxide synthase (NOS) through increased gene transcription. These findings suggest estrogen may provide dual protection against coronary artery disease. First, by increasing endothelium-derived NO, estrogen minimizes the response to contractile agonists released during thrombus formation. And second, by inhibiting vascular smooth muscle (VSM) cell and stimulating endothelial cell proliferation, estrogen slows the development of atherosclerosis. Thus, we hypothesize that estrogen exerts a protective effect on the coronary circulation via its augmentation of NOS and guanylate cyclase activities. The experiments proposed to test this hypothesis utilize isolated hearts, coronary arteries, and cultured cells to study the physiology, biochemistry and molecular biology of gender differences. First, we will examine the role of the NO/cGMP pathway in regulating intracellular Ca2+ and coronary artery reactivity by estrogen using both biochemical measurements of NOS and guanylate cyclase and by the application of specific inhibitors to isolated coronary artery rings. Second, we will confirm the induction of the nos-genes by estradiol and determine which nos-genes are induced using Northern/Dot blot analyses. Third, we will localize the site of nos-mRNA synthesis by in situ hybridization using guinea pig sequence specific probes developed in our laboratory. Finally, since elastin has been shown to contribute to arterial wall thickening, we will investigate the effect of estrogen on elastin gene induction as well as cell growth and proliferation of VSM. The investigation will be carried out over five years using sexually mature (intact and surgically castrated) male and female guinea pigs and will provide new evidence for the role of estrogen in modulating coronary artery reactivity via the NO/cGMP pathway.