Hypoxic vasospasm and/or thrombosis of the major coronary arteries may be instrumental in the development of both transient myocardial ischemia and fatal infarction. Recent evidence further indicates that the vascular endothelium may be an important modulator of coronary artery reactivity. Although many factors have been postulated to contribute to coronary vasospasm, relatively little is known about 1) their relative importance; 2) the appropriate vasoconstrictor stimuli and their origins; and 3) the mechanism by which coronary vasospasm is initiated. Furthermore, it is unclear to what extent coronary vasospasm can be induced by thrombus formation and/or the metabolic products of the thrombus. Conversely, it is not known whether coronary vasospasm could induce thrombus formation in the coronary arteries. This proposal will specifically address these important questions; our overall goal is to investigate in a collaborative effort, the interrelationships between hypoxic coronary vasospasm and thrombosis with emphasis on the role that the endothelial cell plays in modulating these events. In initial experiments, we have found that bovine aortic endothelial cells in culture synthesize and secrete a polypeptide which produces a sustained contraction of the isolated bovine, porcine or canine coronary artery. Also, it is now evident that hypoxic vasoconstriction in canine coronary arteries is dependent on the presence of an intact endothelial layer. The contraction may be mediated by a polypeptide secreted by the endothelial cells, for inhibitors to all of the major coronary agonist-receptor systems and to arachidonate metabolism did not affect the response to hypoxia. In addition, we have found that endothelial cells cultured in a hypoxic or acidotic environment secrete significantly less of the fibrinolytic activator protein - a condition which could favor thrombosis. These new findings and others dealing with mechanisms of hypoxic vasoconstriction, form the basis of our proposal. These findings are significant in that they provide a potentially important role for endothelial cell secretions in modulating thrombosis and coronary artery reactivity and/or responsiveness to hypoxic vasoconstriction. The proposed experiments with coronary vascular smooth muscle will utilize isolated rings derived from different segments of the major bovine and porcine epicardial arteries. Selected parameters of bovine endothelial cell function will be studied using primary cultures of aortic, coronary or left ventricular endothelial cells. This collaborative effort from two laboratories within the same department is likely to provide new and meaningful information which is relevant to our understanding and treatment of coronary artery disease.
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