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

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... d 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 hypoxiaresponse 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.