Abstract
Thalidomide is used in clinical practice to treat gastrointestinal vascular malformation (GIVM), but the pathogenesis of GIVM is not clear. Hypoxia inducible factor 1 alpha (HIF-1α) and 2 alpha (HIF-2α/EPAS1) are in the same family and act as master regulators of the adaptive response to hypoxia. HIF-1α and HIF-2α are up-regulated in vascular malformations in intestinal tissues from GIVM patients, but not in adjacent normal vessels. Therefore, we investigated the role of HIF-1α and HIF-2α during angiogenesis and the mechanism of thalidomide action. In vitro experiments confirmed that vascular endothelial growth factor (VEGF) was a direct target of HIF-2α and that HIF-1α and HIF-2α regulated NOTCH1, Ang2, and DLL4, which enhanced vessel-forming of endothelial cells. Thalidomide down-regulated the expression of HIF-1α and HIF-2α and inhibited angiogenesis. In vivo zebrafish experiments suggested that HIF-2α overexpression was associated with abnormal subintestinal vascular (SIV) sprouting, which was reversed by thalidomide. This result indicated that thalidomide regulated angiogenesis via the inhibition of HIF-1α and HIF-2α expression, which further regulated downstream factors, including VEGF, NOTCH1, DLL4, and Ang2. The abnormally high expression of HIF-1α and HIF-2α may contribute to GIVM.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptor Proteins, Signal Transducing
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Adult
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Aged
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Angiogenesis Inhibitors / administration & dosage*
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Angiogenesis Inhibitors / pharmacology
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Animals
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Basic Helix-Loop-Helix Transcription Factors / genetics*
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Basic Helix-Loop-Helix Transcription Factors / metabolism
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Calcium-Binding Proteins
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Disease Models, Animal
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Female
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Gastrointestinal Hemorrhage / drug therapy*
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Gastrointestinal Hemorrhage / genetics
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Gastrointestinal Hemorrhage / metabolism
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Human Umbilical Vein Endothelial Cells
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Humans
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Hypoxia-Inducible Factor 1, alpha Subunit / genetics*
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Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
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Intercellular Signaling Peptides and Proteins / metabolism
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Male
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Mice
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Middle Aged
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Receptor, Notch1 / metabolism
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Thalidomide / administration & dosage*
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Thalidomide / pharmacology
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Up-Regulation / drug effects
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Vascular Endothelial Growth Factor A / metabolism
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Vascular Malformations / drug therapy*
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Vascular Malformations / genetics
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Vascular Malformations / metabolism
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Vesicular Transport Proteins / metabolism
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Zebrafish
Substances
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Adaptor Proteins, Signal Transducing
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Angiogenesis Inhibitors
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Basic Helix-Loop-Helix Transcription Factors
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Calcium-Binding Proteins
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DLL4 protein, human
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HIF1A protein, human
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Hypoxia-Inducible Factor 1, alpha Subunit
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Intercellular Signaling Peptides and Proteins
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NOTCH1 protein, human
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Receptor, Notch1
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VEGFA protein, human
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VPS51 protein, human
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Vascular Endothelial Growth Factor A
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Vesicular Transport Proteins
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endothelial PAS domain-containing protein 1
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Thalidomide