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J. Biol. Chem., Vol. 283, Issue 27, 18926-18936, July 4, 2008

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Hypoxia-inducible Transcription Factor-2 in Endothelial Cells Regulates Tumor Neovascularization through Activation of Ephrin A1^*

Toshiharu Yamashita, Kinuko Ohneda^¶, Masumi Nagano, Chika Miyoshi^||**, Naomi Kaneko^||**, Yoshihiro Miwa, Masayuki Yamamoto^||**, Osamu Ohneda¹, and Yoshiaki Fujii-Kuriyama^||2

From the Department of Regenerative Medicine, Department of Molecular and Developmental Biology, ^||Center for Tsukuba Advanced Research Alliance, ^**Japan Science and Technology-Exploratory Research for Advanced Technology Environmental Response Project, the Department of Molecular Pharmacology and Japan Science and Technology-Solution-oriented Research for Science and Technology Project, University of Tsukuba, 1-1-1 Tennoudai, Tsukuba 305-8575 and ^¶Laboratory of Molecular Pathophysiology, Faculty of Pharmacy, Takasaki University of Health and Welfare, 60 Nakaorui-machi, Takasaki 370-0033, Japan

The hypoxia-inducible transcription factors (HIF)-1 and -2 mediate responses to hypoxia, such as tumor neovascularization. To determine the function of HIF-2 in vascular endothelial cells (ECs), we examined vascular formation in HIF-2 knockdown (kd/kd) mice transplanted with tumors. We observed that both the tumor size and the number of large vessels growing within transplanted melanomas were significantly reduced in kd/kd recipients compared with wild-type (WT) mice. In contrast, we observed a similar extent of vascular formation within fibrosarcomas transplanted from either kd/kd or WT mice into WT recipients. Thus, HIF-2 expression in host animal ECs, but not in the tumor cells, is crucial for tumor neovascularization. HIF-2 may function through ephrin A1 as the expression of ephrin A1 and related genes was markedly reduced in kd/kd ECs, and HIF-2 specifically bound a hypoxia-response element sequence in the ephrin A1 promoter. Treatment of WT ECs with an ephrin A1 inhibitor (ephrin A1-Fc) also impaired neovascularization. We conclude that in ECs, HIF-2 plays an essential role in vascular remodeling during tumor vascularization through activation of at least ephrin A1.

Received for publication, November 7, 2007 , and in revised form, March 31, 2008.

^* This work was supported in part by grants from Solution-oriented Research for Science and Technology Project, the Japan Science and Technology Agency, and the Scientific Research of the Ministry of Health, Labor, and Welfare of Japan. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence and requests for materials may be addressed. Tel.: 81-29-853-7322; Fax: 81-29-853-7318; E-mail: oohneda{at}md.tsukuba.ac.jp. ² To whom correspondence and requests for materials may be addressed. Tel.: 81-29-853-7322; Fax: 81-29-853-7318; E-mail: ykfujii{at}tara.tsukuba.ac.jp.

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