Thrombin enhances soluble fms-like tyrosine kinase-1 expression in trophoblasts Possible involvement in the pathogenesis of preeclampsia

Thrombin enhances the secretion of sFlt-1 from trophoblasts, indicating that increased thrombin in the uteroplacental interface may contribute to the pathogenesis of preeclampsia.

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Yin Zhao, M.D., Ph.D., Kaori Koga, M.D., Ph.D., Yutaka Osuga , M.D., Ph.D., Miwako Nagai, M.D.; Gentaro Izumi, M.D., Masashi Takamura, M.D., Miyuki Harada, M.D., Ph.D., Yasushi Hirota, M.D., Ph.D., Osamu Yoshino, M.D., Ph.D., Yuji Taketani, M.D., Ph.D.

Vol 98, Issue 4, Pages 917-921



To investigate the possible impact of thrombin on soluble fms-like tyrosine kinase-1 (sFlt-1) expression in trophoblasts




University hospital laboratory.


A trophoblast cell line (HRT-8/SVneo) was treated with thrombin, protease-activated receptor-1 (PAR-1)-specific agonist SFLLERN, and thrombin antagonist PPACK.

Main Outcome Measure(s):

mRNA expression of slft-1, Vascular Endothelial Growth Factor (VEGF) and Placental Growth Factor (PlGF) in trophoblasts, using real-time PCR. The secretion of sFlt-1, VEGF and PlGF protein from trophoblasts, using Enzyme-Linked Immuno Sorbent Assay (ELISA).


Administration of thrombin (10U/ml) and PAR-1 specific agonist SFLLRN (300 M) increased sFlt-1 mRNA expression (4.24 ± 0.74 and 4.21 ± 0.79 fold, respectively, P < 0.05) and protein secretion (5.08 ± 0.42 fold, P < 0.001 and 1.89 ± 0.16 fold, P < 0.05, respectively) in HRT-8/SVneo. The induction of sFlt-1 protein secretion by thrombin was dose dependent. The effect of thrombin was completely reduced by thrombin inhibitor PPACK. Thrombin increased mRNA expression of VEGF (P < 0.05) but did not change VEGF secretion and PlGF mRNA expression and secretion. Conclusion(s):

During placental development, thrombin, generated in the local hemorrhage of the utero-placenta increases trophoblast expression of sFlt-1. Consequently, thrombin may contribute to the pathogenesis of preeclampsia.

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Fertility and Sterility

Editorial Office, American Society for Reproductive Medicine

Fertility and Sterility® is an international journal for obstetricians, gynecologists, reproductive endocrinologists, urologists, basic scientists and others who treat and investigate problems of infertility and human reproductive disorders.