| Opposing roles for HIF-1α and HIF-2α in the regulation of angiogenesis by mononuclear phagocytes. | |
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MedLine Citation:
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PMID: 20952691 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Macrophages contribute to tumor growth through the secretion of the proangiogenic molecule vascular endothelial growth factor (VEGF). We previously observed that monocytes treated with the cytokine granulocyte-macrophage colony-stimulating factor (GM-CSF) produce a soluble form of the VEGF receptor-1 (sVEGFR-1), which neutralizes VEGF biologic activity. The VEGF and VEGFR-1 promoters both contain a hypoxia regulatory element, which binds the hypoxia-inducible factor (HIF) transcription factors under hypoxic conditions. Based on this observation, we examined VEGF and sVEGFR-1 production from monocytes cultured at various O(2) concentrations. The amount of sVEGFR-1 production observed from GM-CSF-treated monocytes increased with decreasing levels of O(2). This sVEGFR-1 was biologically active and sequestered VEGF. To evaluate the role of the HIFs in sVEGFR-1 production, we used macrophages with a genetic deletion of HIF-1α. HIF-1α(-/-) macrophages cultured with GM-CSF at hypoxia secreted diminished amounts of VEGF compared with HIF-1α(+/+) macrophages, whereas sVEGFR-1 secretion was unaffected. In contrast, siRNA-mediated knockdown of HIF-2α inhibited the production of sVEGFR-1 in response to GM-CSF and low O(2), whereas VEGF production was unaffected. These studies suggest that hypoxia, generally thought to promote angiogenesis, can induce antiangiogenic behavior from macrophages within a GM-CSF-rich environment. Furthermore, these results suggest specific and independent roles for HIF-1α and HIF-2α in hypoxic macrophages. |
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Authors:
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Tim D Eubank; Julie M Roda; Haowen Liu; Todd O'Neil; Clay B Marsh |
Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural Date: 2010-10-15 |
Journal Detail:
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Title: Blood Volume: 117 ISSN: 1528-0020 ISO Abbreviation: Blood Publication Date: 2011 Jan |
Date Detail:
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Created Date: 2011-01-07 Completed Date: 2011-02-24 Revised Date: 2012-01-06 |
Medline Journal Info:
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Nlm Unique ID: 7603509 Medline TA: Blood Country: United States |
Other Details:
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Languages: eng Pagination: 323-32 Citation Subset: AIM; IM |
Affiliation:
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Dorothy M. Davis Heart and Lung Research Institute, Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine, Department of Internal Medicine, Ohio State University College of Medicine, Columbus, OH 43210, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Animals Anoxia / metabolism* Basic Helix-Loop-Helix Transcription Factors / physiology* Blotting, Western Endothelium, Vascular / metabolism* Flow Cytometry Granulocyte-Macrophage Colony-Stimulating Factor / genetics, metabolism Humans Hypoxia-Inducible Factor 1, alpha Subunit / physiology* Macrophages / metabolism Mice Mice, Inbred C57BL Mice, Knockout Monocytes / metabolism Mononuclear Phagocyte System / metabolism* Neovascularization, Physiologic / physiology* RNA, Messenger / genetics RNA, Small Interfering / genetics Reverse Transcriptase Polymerase Chain Reaction STAT5 Transcription Factor Umbilical Veins / cytology Vascular Endothelial Growth Factor A / genetics, metabolism Vascular Endothelial Growth Factor Receptor-1 / genetics, metabolism |
| Grant Support | |
ID/Acronym/Agency:
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K99 CA131552-01/CA/NCI NIH HHS; R01 HL067167/HL/NHLBI NIH HHS; T32 HL07946-06/HL/NHLBI NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Basic Helix-Loop-Helix Transcription Factors; 0/Hif1a protein, mouse; 0/Hypoxia-Inducible Factor 1, alpha Subunit; 0/RNA, Messenger; 0/RNA, Small Interfering; 0/STAT5 Transcription Factor; 0/Vascular Endothelial Growth Factor A; 0/endothelial PAS domain-containing protein 1; 83869-56-1/Granulocyte-Macrophage Colony-Stimulating Factor; EC 2.7.10.1/Vascular Endothelial Growth Factor Receptor-1 |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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