The vascular endothelium plays several critical roles in the regulation of endogenous fibrinolytic activity, including the following: 1) it serves as the major site of synthesis and secretion of tissue-type plasminogen activator (t-PA), which is the most important activator of plasminogen in plasma; 2) it is a major producer of plasminogen activator inhibitor-1 (PAI-1), which is the major physiologic inhibitor of t-PA in plasma; and 3) it expresses receptors that bind plasminogen activators and plasminogen, and these receptors appear to localize and to enhance fibrinolytic activity. Although a wide variety of biological compounds have been identified that can induce the production of t-PA and/or PAI-1 by cultured endothelium, there is little data available at present that specifically describes the effects of estrogen on endothelial fibrinolytic balance. However, epidemiologic data indicate that premenopausal women are relatively protected from the development of coronary artery disease. Furthermore, recent studies have demonstrated that the administration of estrogens to postmenopausal women reduces the incidence of cardiovascular disease. One of the potential mechanisms whereby estrogen may contribute to the prevention of cardiovascular disease is by exerting a positive influence on endothelial fibrinolytic balance. We have hypothesized that estrogens may promote fibrinolytic activity by stimulating the production oft-PA (or u-PA), enhancing the expression of receptors that bind t-PA, u- PA, and/or plasminogen, or by suppressing the production of PAI-1. We suggest that these effects may contribute to the diminished expression of ischemic cardiovascular disease in premenopausal women or in postmenopausal women treated with estrogen supplementation. This project is designed to test the hypothesis that estrogen plays a role in the regulation of endothelial fibrinolysis through one or more of the potential mechanisms described above.
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