Yamashita T, Ohneda K, Nagano M, Miyoshi C, Kaneko N, Miwa Y, Yamamoto M, Ohneda O, Fujii-Kuriyama Y
HIF-2alpha in endothelial cells regulates tumor neovascularization through activation of ephrin A1. [JOURNAL ARTICLE]
J Biol Chem 2008 Apr 23.
The hypoxia-inducible transcription factors HIF-1alpha and HIF-2alpha mediate responses to hypoxia, such as tumor neovascularization. To determine the function of HIF-2alpha in vascular endothelial cells (ECs), we examined vascular formation in HIF-2alpha 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 to 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-2alpha expression in host animal ECs, but not in the tumor cells, is crucial for tumor neovascularization. HIF-2alpha may function through as at least ephrin A1 since the expression of ephrin A1 and related genes was markedly reduced in kd/kd ECs and HIF-2alpha 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-2alpha plays an essential role in vascular remodeling during tumor vascularization through activation of at least ephrin A1.
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