Abstract
We deleted the hypoxia-responsive transcription factor HIF-1alpha in endothelial cells (EC) to determine its role during neovascularization. We found that loss of HIF-1alpha inhibits a number of important parameters of EC behavior during angiogenesis: these include proliferation, chemotaxis, extracellular matrix penetration, and wound healing. Most strikingly, loss of HIF-1alpha in EC results in a profound inhibition of blood vessel growth in solid tumors. These phenomena are all linked to a decreased level of VEGF expression and loss of autocrine response of VEGFR-2 in HIF-1alpha null EC. We thus show that a HIF-1alpha-driven, VEGF-mediated autocrine loop in EC is an essential component of solid tumor angiogenesis.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Cell Hypoxia
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Cell Proliferation
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Cells, Cultured
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Chemotaxis
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Endothelial Cells / pathology
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Gene Expression Regulation
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Hypoxia-Inducible Factor 1, alpha Subunit
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Mice
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Neoplasms / blood supply*
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Neoplasms / metabolism*
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Neoplasms / pathology
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Neovascularization, Pathologic*
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Transcription Factors / genetics
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Transcription Factors / physiology*
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Vascular Endothelial Growth Factor A / metabolism*
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Vascular Endothelial Growth Factor Receptor-2 / metabolism
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Wound Healing
Substances
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Hypoxia-Inducible Factor 1, alpha Subunit
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Transcription Factors
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Vascular Endothelial Growth Factor A
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vascular endothelial growth factor A, mouse
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Vascular Endothelial Growth Factor Receptor-2