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Severe Preeclampsia-Related Changes in Gene Expression at the Maternal-Fetal Interface Include Sialic Acid-Binding Immunoglobulin-Like Lectin-6 and Pappalysin-2

Departments of Obstetrics, Gynecology, and Reproductive Sciences (V.D.W., M.G., R.H.-K.), Cell and Tissue Biology (R.H.-K., S.J.F.), Medicine Lung Biology Center (A.C.P., R.-F.Y.), and Anatomy and Pharmaceutical Chemistry (S.J.F.), University of California, San Francisco, San Francisco, California 94143; Department of Obstetrics and Gynecology (V.D.W., A.K., K.K.R.), University of Colorado Denver, Aurora, Colorado 80045; Department of Molecular and Cellular Medicine (A.V.), University of California, San Diego, San Diego, California 92093; and Department of Molecular Biology (K.K.-S., M.T.O., C.O.), University of Aarhus, DK-8000 Aarhus C, Denmark

Address all correspondence and requests for reprints to: Virginia D. Winn, M.D., Ph.D., University of Colorado Denver, Department of Obstetrics and Gynecology, Reproductive Sciences, Mail Stop 8309, 12800 East 19th Avenue, P.O. Box 6511, Aurora, Colorado 80045. E-mail: Virginia.Winn{at}ucdenver.edu.

Preeclampsia (PE), which affects 4–8% of human pregnancies, causes significant maternal and neonatal morbidity and mortality. Within the basal plate, placental cytotrophoblasts (CTBs) of fetal origin invade the uterus and extensively remodel the maternal vasculature. In PE, CTB invasion is often shallow, and vascular remodeling is rudimentary. To better understand possible causes, we conducted a global analysis of gene expression at the maternal-fetal interface in placental samples from women with PE (n = 12; 24–36 wk) vs. samples from women who delivered due to preterm labor with no evidence of infection (n = 11; 24–36 wk), a condition that our previous work showed is associated with normal CTB invasion. Using the HG-U133A&B Affymetrix GeneChip platform, and statistical significance set at log odds-ratio of B >0, 55 genes were differentially expressed in PE. They encoded proteins previously associated with PE [e.g. Flt-1 (vascular endothelial growth factor receptor-1), leptin, CRH, and inhibin] and novel molecules [e.g. sialic acid binding Ig-like lectin 6 (Siglec-6), a potential leptin receptor, and pappalysin-2 (PAPP-A2), a protease that cleaves IGF-binding proteins]. We used quantitative PCR to validate the expression patterns of a subset of the genes. At the protein level, we confirmed PE-related changes in the expression of Siglec-6 and PAPP-A2, which localized to invasive CTBs and syncytiotrophoblasts. Notably, Siglec-6 placental expression is uniquely human, as is spontaneous PE. The functional significance of these novel observations may provide new insights into the pathogenesis of PE, and assaying the circulating levels of these proteins could have clinical utility for predicting and/or diagnosing PE.