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Hypoxia-Inducible Factor-1 Transactivates Transforming Growth Factor-ß3 in Trophoblast

Department of Obstetrics and Gynecology (H.N., T.N., M.H., Y.O., O.I., K.I.), Tokyo Medical University, Tokyo 160-0023, Japan; Laboratory of Human Carcinogenesis (L.E.H.), National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892-4255

Address all correspondence and requests for reprints to: Hirotaka Nishi, M.D., Ph.D., Department of Obstetrics and Gynecology, Tokyo Medical University, 6-7-1 Nishishinjuku Shinjuku, Tokyo 160-0023, Japan. E-mail: nishih{at}tokyo-med.ac.jp.

Hypoxia occurs during the development of placenta in the first trimester and is implicated in trophoblast differentiation. Intervillous blood flow increases after 10 wk of gestation and results in exposure of trophoblast cells to oxygen. Before this time, low oxygen appears to prevent trophoblast differentiation toward an invasive phenotype. The oxygen-regulated early events of trophoblast differentiation are mediated by TGF-ß3. TGF-ß3 plays a vital role in trophoblast differentiation, and its overexpression can be found in preeclamptic placenta. We sought to determine the mechanism of TGF-ß3 expression through hypoxia-inducible factor (HIF)-1. We show that HIF-1 and TGF-ß3 are overexpressed in preeclamptic placenta. Hypoxia not only transactivates the TGF-ß3 promoter activity but also enhances endogenous TGF-ß3 expression. Using the TGF-ß3 promoter deletion mutants, we show that the region between –90 and –60, which contains a putative HIF-1 consensus motif, is crucial for HIF-1-mediated transactivation. Electrophoretic mobility shift assays show that HIF-1 binds to the oligonucleotide containing the HIF-1 motif. Also, introduction of an antisense oligonucleotide for HIF-1 diminishes TGF-ß3 expression during hypoxia, indicating that the up-regulation of TGF-ß3 by hypoxia is mediated through HIF-1. Our results provide evidence that regulation of TGF-ß3 promoter activity by HIF-1 represents a mechanism for trophoblast differentiation during hypoxia.

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