Hypoxia-inducible transcription factor-2α 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 Ohneda, Yoshiaki Fujii-Kuriyama

Research output: Contribution to journalArticlepeer-review

62 Citations (Scopus)

Abstract

The hypoxia-inducible transcription factors (HIF)-1α and -2α mediate responses to hypoxia, such as tumor neovascularization. To determine the function of HIF-2α in vascular endothelial cells (ECs), we examined vascular formation in HIF-2α 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-2α expression in host animal ECs, but not in the tumor cells, is crucial for tumor neovascularization. HIF-2α may function through ephrin A1 as the expression of ephrin A1 and related genes was markedly reduced in kd/kd ECs, and HIF-2α specifically bound a hypoxia-response element sequence in the ephrin A1 promoter. Treatment of WTECs with an ephrin A1 inhibitor (ephrin A1-Fc) also impaired neovascularization. We conclude that in ECs, HIF-2α plays an essential role in vascular remodeling during tumor vascularization through activation of at least ephrin A1.

Original languageEnglish
Pages (from-to)18926-18936
Number of pages11
JournalJournal of Biological Chemistry
Volume283
Issue number27
DOIs
Publication statusPublished - 2008 Jul 4

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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