Hypoxia-inducible transcription factor-2alpha in endothelial cells regulates tumor neovascularization through activation of ephrin A1.
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.
Yamashita
Toshiharu
T
Department of Regenerative Medicine, University of Tsukuba, 1-1-1 Tennoudai, Tsukuba 305-8575, Japan.
Ohneda
Kinuko
K
Nagano
Masumi
M
Miyoshi
Chika
C
Kaneko
Naomi
N
Miwa
Yoshihiro
Y
Yamamoto
Masayuki
M
Ohneda
Osamu
O
Fujii-Kuriyama
Yoshiaki
Y
D000818:Animals; D042783:Endothelial Cells / Q000378:metabolism* / Q000473:pathology; D036382:Ephrin-A1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008545:Melanoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D011401:Promoter Regions, Genetic / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
D036382:Ephrin-A1; C485502:HIF-2 protein, mouse; C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009363:Neoplasm Proteins; D014157:Transcription Factors