Introduction: Preeclampsia is a serious obstetrical syndrome characterized by hypertension, proteinuria, generalized edema and generalized vasospasm, which affects ~7% of pregnant women. Despite its recognition since antiquity, the current treatment of this disorder is not based on an understanding of its pathophysiology but remains empricial: delivery of the fetus and placenta. The high maternal and fetal morbidity and mortality associated with preeclampsia largely result from the iatrogenic preterm interruption of affected pregnancies. The cellular and molecular biology that underlies this syndrome only recently has begun to be elucidated. Abnormalities of trophoblast differentiation and invasion have been discovered by Dr. Fisher and colleagues. Studies in my laboratory have focused on mechanisms of maternal vascular endothelial dysfunction in preeclampsia, with an emphasis on the biochemical pathways involved in abnormal prostanoid production. Data from our laboratory and those of others indicate that a preponderance of vasoconstrictor prostanoids are produced in vessels and tissues frompreeclamptic women. Methods and Results: We have selected a bioassay (acute release of human umbilical vein endothelial cell prostaglandins) as a paradigm to identify the placenta- and plasma-derived factors responsible for endothelial cell activation in preeclampsia. Our data indicate that the enzyme responsible for prostaglandin synthesis in activated endothelial cells is a member of the family of phospholipases A2. Assays of enzyme activity and immunoblotting of specific PLA2 isoforms are in progress to characterize the enzyme(s) induced in activated cells. Fatty acid substrate transport in the circulation by albumin isoforms, and ultimately into maternal endothelial cells, also appears to be abnormal in preeclampsia. Using isoelectric focusing we haveshown that plasma concentrations of pI=4.8 albumin, an isoform that is relatively rich in fatty acids, are increased significantly in women with preeclampsia compared to normal pregnant controls. We propose that specific fatty acids bound to plasma albumin are the precursors responsible for increased prostaglandin production. Mass spectroscopy will be used to identify the fatty acids associated with plasma albumin isolated from preeclamptic and normal pregnant women. Discussion: The proposed studies will characterize the substrates and enzymes which perturb prostaglandin biosynthesis in preeclampsia. An understanding of these molecules should provide targets for the future development of novel therapeutic antagonists for the rational treatment and possible prophylaxis of preeclampsia.
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