Testosterone has been identified as a potential cardiovascular risk factor for males and heart attacks have been reported in young athletes abusing anabolic steroids. Thromboxane A2 aggregates platelets, constricts vascular smooth muscle and its synthesis is increased in acute coronary artery syndromes. Treatment of cultured rat aortic smooth muscle cells or rats with testosterone results in a significant increase in both smooth muscle and platelet Thromboxane A2 receptors and their responses to Thromboxane A2 mimetics. Treatment of male guinea pigs with testosterone enhances sensitivity and maximal responsiveness of perfused coronary arteries to a Thromboxane A2 mimetic compared to controls. Treatment of normal male volunteers with testosterone doubled their platelet TXA2 receptor density. This proposal will test the hypothesis that testosterone regulates the expression of TXA2 receptors in human platelets and vascular smooth muscle. The molecular mechanism by which testosterone increases the expression of TXA receptors in cultured smooth muscle cells will be determined. Also, the mechanism for the difference in the response to testosterone of male versus female rat aortic smooth cells will be investigated. The effects of administration of testosterone to normal male volunteers and chemical and surgical castration in prostatic cancer patients on platelet Thromboxane A2 receptor density and aggregation responses will be measured. The effects of administration of supplemental testosterone on TXA2 activation of vascular responses in normal males will be determined; in addition, experiments aimed at measuring expression of TXA2 receptors and aggregation responses on platelets of boys and girls at puberty will be conducted; similar experiments in pre- and post-menopausal females and age matched males will be conducted. The goal of all these studies is to provide new information concerning the potential role of testosterone to regulate the expression of Thromboxane A2 receptors and modulate platelet and vascular reactivity in humans.
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