Reduced fetoplacental blood flow has been observed in pregnancies complicated by hypertension, asymmetric intrauterine growth retardation and poorly-controlled diabetes. Vascular tone in fetoplacental resistance vessels is under the control of hormones and autacoids. Recent studies have suggested that the vasoconstrictor, thromboxane, may be increased in high-risk pregnancies. The objective of this investigation is to study the role of thromboxane as an endogenous modulator of fetoplacental vascular resistance in humans, and to study its potential role in pathological states associated with decreased fetoplacental blood flow. The vasoconstrictor action of thromboxane is dependent on its local production, the presence of specific high affinity receptor sites, and post-receptor coupling to effector mechanisms to cause vasoconstriction. We will study the production of thromboxane (and other cyclooxygenase, and lipoxygense products) as measured on the fetal side of the isolated perfused placental cotyledon, characterize thromboxane receptor sites using ligand binding techniques, and study fetoplacental vascular responsiveness to thromboxane. We will test the hypothesis that abnormalities in thromboxane production, metabolism or actions in the placenta account for increased fetoplacental vascular resistance in pregnancies complicated by pregnancy-induced hypertension (PIH), asymmetric intrauterine growth retardation (IUGR) or poorly-controlled diabetes mellitus (DM). Techniques will include: (1) measurement of vascular resistance on the fetal side of the isolated perfused placental cotyledon, (2) the study of thromboxane A2 binding sites in placental membranes, and (3) the measurement of placental eicosanoid synthesis using C(14)-arachidonic acid. The long-term goal of this investigation is to elucidate the mechanisms which account for decreased fetoplacental blood flow, intrauterine growth retardation and fetal abnormalities in pathological human pregnancies. These studies may ultimately lead to a pharmacological rationale for treating disorders of the fetoplacental circulation.
