Preeclampsia is a major cause of maternal and fetal mortality and morbidity affecting 7% of pregnant women. The cause of preeclampsia is unknown but certain concepts are definitively established. The disease primarily affects women in first pregnancies and requires at least the presence of a placenta. Placentation is deficient with reduced trophoblast invasion. Decidual vessels, occluded by fibrin and surrounded by foam cell infiltrates, resemble vessels in allograft rejection which, with the occurrence primarily in first pregnancies, suggests an immunological component. We propose to study the role, mechanism and consequences of maternal-fetal interactions in this abnormal implantation. Autocrine regulation (fetal cells) and paracrine regulation (maternal decidual cells) of trophoblast invasion will be examined in vitro and confirmed by immunocytochemical examination of placental bed biopsies. A similar approach tests the relevance of such regulation to preeclampsia. the impact of reduced trophoblast invasion and hence perfusion by maternal blood on cytotrophoblast function will be tested by examining the effect of trophoblast hypoxia in vitro upon the expression of molecules relevant to invasion. Abnormal implantation reduces uteroplacental perfusion and the ensuing fetal/placental ischemia produces clinically evident preeclampsia with reduced perfusion of virtually all organs. Reduced systemic perfusion is felt to be due to vasoconstriction and microthrombi produced by activation f the coagulation cascade. Evidence is accumulating that this maternal syndrome results from the release of a factor(s) from the ischemic fetal- placental unit, which cause dysfunction of the maternal endothelium. In the proposed studies we will search for the origin, identity and targets of this factor(s). We will test alternate but not mutually exclusive hypotheses that the material arises from trophoblast and/or is a fetal response (from tissues other than trophoblast). In both cases we propose this is secondary to ischemia. This will be directly tested by examining the release of antiendothelial activities from hypoxic trophoblasts in vitro and fetal sheep rendered ischemic in vivo. As indirect evidence we will compare these activities in human umbilical arterial and venous blood. The origin from trophoblast in response to maternal decidua trophoblast interactions will be tested by examining release of activities during co-culture of decidual and trophoblast cells. We will also seek to identify this factor(s) by purification from maternal plasma using endpoints of endothelial cell activation in vitro established in these and previous studies. Certain targets in endothelial cells seem especially relevant. Thus we will test whether maternal serum contains factors which enhance endothelial cell lipoperoxidation or act to down regulate the production of the mediator, nitric oxide (NO) by these cells. This ambitious program, based in three centers, brings together relevant expertise from around the world to address the pathogenesis of preeclampsia with modern biological techniques.
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