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Metal Transcription Factor-1 Is Involved in Hypoxia-Dependent Regulation of Placenta Growth Factor in Trophoblast-Derived Cells

Department of Obstetrics and Gynecology (F.N., M.S., R.M., A.M., A.I., T.T., E.I., K.S., K.M., T.K.), Osaka University Faculty of Medicine, Osaka 565-0871, Japan; Osaka Medical Center and Research Institute for Maternal and Child Health (Y.O.), Osaka 594-1101, Japan; and Sakai Municipal Hospital (T.Y.), Osaka 591-0064, 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 City, Osaka 565-0871, Japan. E-mail: msakata{at}gyne.med.osaka-u.ac.jp.

Placenta growth factor (PlGF) is a placental angiogenic factor. Metal-responsive transcription factor (MTF)-1 was reported to take part in the hypoxic induction of PlGF in RAS-transformed mouse fibroblasts. We contrarily showed that PlGF mRNA and protein levels decreased under hypoxia in a choriocarcinoma BeWo cell line derived from trophoblast. In this report, we examined whether hypoxia-dependent regulation of the PlGF gene in these cells also depends on MTF-1. We analyzed the effect of hypoxia on MTF-1 expression, and it was revealed to be decreased. Moreover, MTF-1 small interfering RNA treatment decreased PlGF mRNA level. To investigate the transcription of PlGF under hypoxia, we cloned promoter region of the human PlGF. Promoter deletion analysis suggested that triple repeats of metal-responsive element located between –511 and –468 bp in the promoter are important for the hypoxic regulation of PlGF. Treatment with MTF-1 small interfering RNA resulted in the significant decreased luciferase activity in PlGF reporter constructs. Chromatin immunoprecipitation showed the binding of the MTF-1 protein to the promoter region. We examined MTF-1 immunoreactivity in trophoblasts of term placental tissue from patients with normal pregnancies and preeclampsia, which represents a condition of placental hypoxia. Immunoreactivity of the MTF-1 protein was decreased in placentas from pregnant women with preeclampsia when compared with those from normal pregnant women. Taken together, these findings suggest that MTF-1 is involved in hypoxia-dependent regulation of PlGF in trophoblast-derived cells.

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