Hypoxia induces vascular endothelial growth factor gene transcription in human osteoblast-like cells through the hypoxia-inducible factor-2alpha

VEGF is produced by osteoblasts and has been postulated to function as an angiogenic stimulus during normal skeletal development and in fracture repair. In this study, we characterized the molecular mechanisms by which experimental hypoxia increases VEGF mRNA in human MG63 osteoblast-like cells. Exp...

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Bibliographic Details
Published in:Endocrinology (Philadelphia) 2001-02, Vol.142 (2), p.959-962
Main Authors: Akeno, N, Czyzyk-Krzeska, M F, Gross, T S, Clemens, T L
Format: Article
Language:English
Subjects:
Basic Helix-Loop-Helix Transcription Factors
Cell Line
Endothelial Growth Factors - genetics
Gene Expression
Humans
Hypoxia - genetics
Lymphokines - genetics
Osteoblasts - physiology
Trans-Activators - physiology
Transcription, Genetic
Vascular Endothelial Growth Factor A
Vascular Endothelial Growth Factors
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Summary:VEGF is produced by osteoblasts and has been postulated to function as an angiogenic stimulus during normal skeletal development and in fracture repair. In this study, we characterized the molecular mechanisms by which experimental hypoxia increases VEGF mRNA in human MG63 osteoblast-like cells. Exposure of MG63 cells to 1% O(2) for 24 h resulted in a four-fold increase in VEGF mRNA. Immunoblotting of nuclear extracts demonstrated a time-dependent increase in the level of the Hif-2alpha protein, which preceded the rise in VEGF mRNA. To determine the effect of hypoxia on VEGF gene transcription, MG63 cells were transiently transfected with a segment of the VEGF promoter construct fused to luciferase and then exposed to 1% O(2). Hypoxia induced VEGF promoter activity five-fold by 24 h. Forced expression of Hif-2alpha, but not Hif-1alpha, increased both basal and hypoxia induced VEGF promoter activity. By contrast, the ability of the VEGF reporter to respond to hypoxia or recombinant Hif-2alpha was abolished in cells transfected with a VEGF promoter construct containing a mutation in the hypoxia response element. In summary, exposure of osteoblast-like cells to hypoxia induces VEGF expression via induction of Hif-2alpha and transcriptional activation of the VEGF promoter.
ISSN:0013-7227