| First Author | Yamashita T | Year | 2008 |
| Journal | J Biol Chem | Volume | 283 |
| Issue | 27 | Pages | 18926-36 |
| PubMed ID | 18434321 | Mgi Jnum | J:138185 |
| Mgi Id | MGI:3804398 | Doi | 10.1074/jbc.M709133200 |
| Citation | Yamashita T, et al. (2008) Hypoxia-inducible transcription factor-2alpha in endothelial cells regulates tumor neovascularization through activation of ephrin A1. J Biol Chem 283(27):18926-36 |
| abstractText | The hypoxia-inducible transcription factors (HIF)-1alpha and -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 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-2alpha expression in host animal ECs, but not in the tumor cells, is crucial for tumor neovascularization. HIF-2alpha may function through ephrin A1 as 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. |
