Vascular resistance in the human fetal-placental circulation may be regulated by humoral agents or paracrine/autocrine factors released in response to some physical (hydrodynamic) or other stimulus. Endothelial-derived vasoactive agents including endothelin-1 (Et-1) or nitric oxide (NO), which is one of the endothelial-derived relaxing factors, have been preliminarily described to act upon the fetal- placental vasculature. The vasoconstrictor actions of Et-1 may be mediated in part by stimulation of release and action of thromboxane A2. Evidence is accruing that there are distinct isoforms of nitric oxide synthetase, the enzyme that forms nitric oxide from the guanidino nitrogen of the semi-essential amino acid, I-arginine, in endothelial and vascular smooth muscle cells. These isoforms may be activated by different stimuli. Production of Et-1 and NO by the fetal-placental vasculature may be altered in pregnancies complicated by pregnancy- induced hypertension/preeclampsia which are characterized by increased fetal-placental vascular resistance and hence reduced blood flow. There is also evidence that these agents may participate in or mediate hypoxia-induced vasoconstriction in some vascular beds. The interaction of Et-1 and NO to regulate-fetal-placental vascular reactivity and their potential for mediating hypoxia-induced vasoconstriction in this circulation have not been studied. Specifically we will study: 1. The effect of alterations in perfusate flow, shear stress or pulse pressure on Et-1 and NO production from the fetal-placental circulation. 2. The role of NO as an antagonist of Et-1 action and the role of thromboxane A2(TXA2) as a mediator of Et-1-induced vasoconstriction using specific inhibitors of synthesis or action of these agents. 3. The participation of increased Et-1 and TXA2 or decreased NO production in modulation of hypoxia-induced vasoconstriction in the fetal-placental circulation. 4. Co-factor requirements and substrate specificity of NO synthetase enzymes in endothelium and vascular smooth muscle and the relative activity of these enzymes in umbilical and chorionic plate arteries and veins in stem villous vessels. 5. NO synthetase activity in umbilical and placental blood vessels and Et-1, TXA2 and NO synthesis and action in the fetal-placental circulation from normotensive pregnancies in comparison with those complicated by pregnancy-induced hypertension/preeclampsia.
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