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Hypoxia Up-Regulates Hypoxia-Inducible Factor-1 Expression through RhoA Activation in Trophoblast Cells

Department of Obstetrics and Gynecology (M.H., M.S., T.T., M.T., R.M., A.I., K.T., Y.M.), Osaka University Faculty of Medicine, Suita, Osaka 565-0871, Japan; and Osaka Medical Center for Cancer and Cardiovascular Diseases (T.Y.), Higashinari-ku, Osaka 537-0025, Japan

Address all correspondence and requests for reprints to: Masahiro Sakata, M.D., Ph.D., Department of Obstetrics and Gynecology, Osaka University, Faculty of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan. E-mail: msakata{at}gyne.med.osaka-u.ac.jp.

During early pregnancy, trophoblast cells are exposed to relatively low-oxygen tension. Recently, the Rho GTPase family has been shown to play a key role in hypoxia-inducible factor-1 (HIF-1) induction in renal cell carcinoma. The present study was designed to investigate the effect of low-oxygen conditions on RhoA expression in trophoblast cells isolated from early stages of human placenta and in trophoblast-derived BeWo cells and JAR cells. Immunoblot and RT-PCR analyses showed that low-oxygen conditions (1% O₂ or 250 µM CoCl₂) stimulated expression of RhoA protein and mRNA. Pull-down assays demonstrated that these low-oxygen conditions increased RhoA activity. Preincubation of BeWo cells with Clostridium botulinum C3 exoenzyme, a specific inhibitor of Rho, inhibited hypoxia-induced HIF-1 expression. Under 1% O₂ or 250 µM CoCl₂, BeWo cells, transfected with a dominant-negative RhoA, exhibited decreased levels of HIF-1 protein and mRNA compared with the control vector transfectants. BeWo cells expressing constitutively active RhoA showed enhanced protein levels of not only HIF-1 but also vascular endothelial growth factor (VEGF) and glucose transporter 1, which are target gene products of HIF-1. These findings suggest that up-regulation of RhoA induced by low-oxygen conditions may play an important role in regulation of HIF-1 expression in trophoblast cells.

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