Thrombin regulates soluble fms-like tyrosine kinase-1 (sFlt-1) expression in first trimester decidua: implications for preeclampsia.
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-1beta 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.
Lockwood
Charles J
CJ
The Anita O'Keefe Young Professor and Chair, Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, 333 Cedar Street, Room 335 FMB, P.O. Box 208063, New Haven, CT, USA.
Toti
Paolo
P
Arcuri
Felice
F
Norwitz
Errol
E
Funai
Edmund F
EF
Huang
Se-Te J
ST
Buchwalder
Lynn F
LF
Krikun
Graciela
G
Schatz
Frederick
F
D002478:Cells, Cultured; D003656:Decidua / Q000166:cytology / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D004958:Estradiol / Q000494:pharmacology; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects*; D006629:Hirudins / Q000494:pharmacology; D006801:Humans; D053583:Interleukin-1beta / Q000494:pharmacology; D008525:Medroxyprogesterone / Q000494:pharmacology; D011225:Pre-Eclampsia / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D011247:Pregnancy; D011261:Pregnancy Trimester, First; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012995:Solubility; D013917:Thrombin / Q000494:pharmacology*; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000235:genetics* / Q000378:metabolism
D006629:Hirudins; D053583:Interleukin-1beta; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D042461:Vascular Endothelial Growth Factor A; D004958:Estradiol; C501162:FLT1 protein, human; D040281:Vascular Endothelial Growth Factor Receptor-1; D013917:Thrombin; D008525:Medroxyprogesterone