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(American Journal of Pathology. 2007;170:1398-1405.)
© 2007 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2007.060465

Thrombin Regulates Soluble fms-Like Tyrosine Kinase-1 (sFlt-1) Expression in First Trimester Decidua

Implications for Preeclampsia

Charles J. Lockwood*, Paolo Toti{dagger}, Felice Arcuri{dagger}, Errol Norwitz*, Edmund F. Funai*, Se-Te J. Huang*, Lynn F. Buchwalder*, Graciela Krikun* and Frederick Schatz*

From the Department of Obstetrics, Gynecology and Reproductive Sciences,* Yale University School of Medicine, New Haven, Connecticut; and the Department of Human Pathology and Oncology,{dagger} University of Siena, Siena, Italy

The primary placental defect in preeclampsia is shallow trophoblast invasion of the decidua leading to incomplete vascular transformation and inadequate uteroplacental perfusion. Soluble fms-like tyrosine kinase-1 (sFlt-1) seems to interfere with these events by inhibiting local angiogenesis and/or by impeding trophoblast invasion. Preeclampsia is also associated with maternal thrombophilias and decidual hemorrhage, which form thrombin from decidual cell-expressed tissue factor. Although sFlt-1 is highly expressed by trophoblasts, sFlt-1 expression has not been studied in decidual cells, which are the predominant cell type encountered by invading trophoblasts. Here, we demonstrate that isolated decidual cells express sFlt-1 mRNA, suggesting that they can synthesize sFlt-1. Moreover, in first trimester decidual cells, thrombin enhanced sFlt-1 mRNA levels, as measured by quantitative reverse transcriptase-polymerase chain reaction, and levels of secreted sFlt-1 protein, as measured by enzyme-linked immunosorbent assay. The thrombin antagonist hirudin blocked this effect, demonstrating that active thrombin is required. Emphasizing the specificity of the thrombin response, neither interleukin-1ß nor tumor necrosis factor-{alpha} affected sFlt-1 expression in the decidual cells. In contrast to first trimester decidual cells, thrombin did not affect sFlt-1 levels in cultured term decidual cells. In early pregnancy, thrombin may act as an autocrine/paracrine enhancer of sFlt-1 expression by decidual cells to promote pre-eclampsia by interfering with local vascular transformation.




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