ENDOTHELIN AND NITRIC OXIDE IN THE PLACENTAL VASCULATURE

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.