The Role of Thromboxane A2 in Vascular Regulation in Women with Endometriosis

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Project Summary CVD is the leading cause of death worldwide. Endometriosis has been repeatedly identified as an independent risk factor for CVD that affects an estimated one in ten women in the world. Endometriosis is a gynecologic condition characterized by invasive extrauterine endometriotic lesions, chronic pain and pain sensitization, and systemic inflammation and is associated with accelerated cardiovascular disease risk. The expression of cyclooxygenase-2, a key enzyme in inflammation, is upregulated in endometriotic lesions as are its metabolites, namely TxA2. TxA2 is a potent vasoconstrictor able to diffuse across the endothelium to act directly on its receptors in the vascular smooth muscle. TxA2 can also antagonize NOS within the endothelial cells, preventing vasodilation. A decrease in nitric oxide (NO)-mediated vasodilation defines endothelial dysfunction and is regarded as a critical early event in the development of atherosclerosis and overt cardiovascular disease. Women with endometriosis demonstrate marked endothelial dysfunction compared with healthy controls. Furthermore, TxA2 receptors (TP) play a key role in sensitizing the sensory afferents in skeletal muscle in pre- clinical models of cardiovascular disease, leading to an exaggerated exercise pressor reflex. This is a strong predictor of major adverse cardiovascular events in cardiovascular disease patients. Therefore, the purpose of this project is twofold: 1) to determine the effect of the TP on the regulation of microvascular function and in circulating platelets in women with endometriosis and 2) to investigate sensory afferent sensitization in women with endometriosis. We hypothesize that women with endometriosis demonstrate exaggerated vasoconstriction to both pharmacological stimuli locally modulating vasomotor tone and to physiological sympathoexcitatory stimuli. This project and associated training plan will serve as a vehicle for exceptional predoctoral training for the candidate.