PUBLICATION
HIF-1α and HIF-2α induced angiogenesis in gastrointestinal vascular malformation and reversed by thalidomide
- Authors
- Feng, N., Chen, H., Fu, S., Bian, Z., Lin, X., Yang, L., Gao, Y., Fang, J., Ge, Z.
- ID
- ZDB-PUB-160602-3
- Date
- 2016
- Source
- Scientific Reports 6: 27280 (Journal)
- Registered Authors
- Keywords
- Intestinal diseases, Mechanisms of disease
- MeSH Terms
-
- Adult
- Aged
- Angiogenesis Inhibitors/administration & dosage*
- Angiogenesis Inhibitors/pharmacology
- Animals
- Basic Helix-Loop-Helix Transcription Factors/genetics*
- Basic Helix-Loop-Helix Transcription Factors/metabolism
- Disease Models, Animal
- Female
- Gastrointestinal Hemorrhage/drug therapy*
- Gastrointestinal Hemorrhage/genetics
- Gastrointestinal Hemorrhage/metabolism
- Human Umbilical Vein Endothelial Cells
- Humans
- Hypoxia-Inducible Factor 1, alpha Subunit/genetics*
- Hypoxia-Inducible Factor 1, alpha Subunit/metabolism
- Intercellular Signaling Peptides and Proteins/metabolism
- Male
- Mice
- Middle Aged
- Receptor, Notch1/metabolism
- Thalidomide/administration & dosage*
- Thalidomide/pharmacology
- Up-Regulation/drug effects
- Vascular Endothelial Growth Factor A/metabolism
- Vascular Malformations/drug therapy*
- Vascular Malformations/genetics
- Vascular Malformations/metabolism
- Vesicular Transport Proteins/metabolism
- Zebrafish
- PubMed
- 27249651 Full text @ Sci. Rep.
Citation
Feng, N., Chen, H., Fu, S., Bian, Z., Lin, X., Yang, L., Gao, Y., Fang, J., Ge, Z. (2016) HIF-1α and HIF-2α induced angiogenesis in gastrointestinal vascular malformation and reversed by thalidomide. Scientific Reports. 6:27280.
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping