The mechanisms responsible for normal maternal cardiovascular adaptation during pregnancy and the alterations in these mechanisms that occur in hypertensive pregnancies are not well understood. There is considerable evidence, however, that prostanoids may be involved since the PGI2/TxA2 ratio is elevated in normal pregnancy and reduced in pregnancies complicated by hypertension. Furthermore, inhibition of prostaglandin production in women and animals has profound effects on the reactivity of the systemic and uterine vascular beds to vasoconstriction by angiotensin 11 and alpha-adrenergic agents. Therefore, the long-term objectives of this project are to determine if the vascular alterations observed in hypertensive pregnancies (preeclampsia/chronic hypertension) are coincident with (or caused by) the alterations in PGI2 and TxA2 production, and what are the resulting cellular and intracellular events. To address this we will utilize in vitro studies of maternal systemic and uterine and fetal placental arteries as well as in vivo studies of the mechanism by which low-dose aspirin treatment affects the progress and maternal and fetal outcomes of hypertensive pregnancies. Using these methods we will define in detail the role of prostaglandins and related cellular events in the control of in vivo vascular reactivity to angiotensin II, in addition to in vitro reactivity to angiotensin II, alpha-adrenergic agents and KCI. The in vitro studies will encompass the effects of these agents on prostaglandin production, calcium and calcium channels, cAMP generation, phosphatidylinositol hydrolysis, and the activity of protein kinase A and C. Studies to examine angiotensin II and alpha1- and alpha2 -adrenergic receptor number and affinity as well as studies of the structural and compliance changes that occur in the arteries of normal and hypertensive pregnant women also are described. By achieving these aims our understanding of normal pregnancy adaptation and the alterations associated with pregnancy-induced hypertension (preeclampsia) will be better understood, thereby improving methods of care for women with this disease.
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