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.

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.

Volume 98, Issue 4, Pages 917-921, October 2012


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.

  • Raul Gomez, PhD, IUIVI

    Congrats to the authors for such an exhaustive analysis of their results and relevant findings in their work . Everything males sense in the context of their hypothesis and what is previously published on preeclampsia. Assuming that preeclampsia is the result of restricted availiability of VEGF induced by increased sVEGFR1 I wonder whether the work had benefited from evaluating the actual availability of VEGF induced by treatments through measuring no tonly total but also the fraction of free VEGF. What do the authors think on this regard? Does my suggestion make in the hte context of their in-vitro experiments or not?
    Thanks for your response in advance

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