title: HIF-1α and HIF-2α induced angiogenesis in gastrointestinal vascular malformation and reversed by thalidomide.
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.
authors.affiliation: Key Laboratory of Gastroenterology &Hepatology, Ministry of Health, Division of Gastroenterology &Hepatology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Diseases, 145 Middle Shandong Road, Shanghai 200001, China.
authors.forename: Nan
authors.initials: N
authors.lastname: Feng
authors.affiliation: Key Laboratory of Gastroenterology &Hepatology, Ministry of Health, Division of Gastroenterology &Hepatology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Diseases, 145 Middle Shandong Road, Shanghai 200001, China.
authors.forename: Haiying
authors.initials: H
authors.lastname: Chen
authors.affiliation: Key Laboratory of Gastroenterology &Hepatology, Ministry of Health, Division of Gastroenterology &Hepatology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Diseases, 145 Middle Shandong Road, Shanghai 200001, China.
authors.forename: Sengwang
authors.initials: S
authors.lastname: Fu
authors.affiliation: Department of gastroenterology and hepatology, Nantong Institute of liver diease, Nantong Third people's Hospital, Nantong 223006, China.
authors.forename: Zhaolian
authors.initials: Z
authors.lastname: Bian
authors.affiliation: Key Laboratory of Gastroenterology &Hepatology, Ministry of Health, Division of Gastroenterology &Hepatology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Diseases, 145 Middle Shandong Road, Shanghai 200001, China.
authors.forename: Xiaolu
authors.initials: X
authors.lastname: Lin
authors.affiliation: Key Laboratory of Gastroenterology &Hepatology, Ministry of Health, Division of Gastroenterology &Hepatology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Diseases, 145 Middle Shandong Road, Shanghai 200001, China.
authors.forename: Li
authors.initials: L
authors.lastname: Yang
authors.affiliation: Key Laboratory of Gastroenterology &Hepatology, Ministry of Health, Division of Gastroenterology &Hepatology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Diseases, 145 Middle Shandong Road, Shanghai 200001, China.
authors.forename: Yunjie
authors.initials: Y
authors.lastname: Gao
authors.affiliation: Key Laboratory of Gastroenterology &Hepatology, Ministry of Health, Division of Gastroenterology &Hepatology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Diseases, 145 Middle Shandong Road, Shanghai 200001, China.
authors.forename: Jingyuan
authors.initials: J
authors.lastname: Fang
authors.affiliation: Key Laboratory of Gastroenterology &Hepatology, Ministry of Health, Division of Gastroenterology &Hepatology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Diseases, 145 Middle Shandong Road, Shanghai 200001, China.
authors.forename: Zhizheng
authors.initials: Z
authors.lastname: Ge
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000328:Adult; D000368:Aged; D020533:Angiogenesis Inhibitors / Q000008:administration & dosage* / Q000494:pharmacology; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics* / Q000378:metabolism; D002135:Calcium-Binding Proteins; D004195:Disease Models, Animal; D005260:Female; D006471:Gastrointestinal Hemorrhage / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics* / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D008297:Male; D051379:Mice; D008875:Middle Aged; D051881:Receptor, Notch1 / Q000378:metabolism; D013792:Thalidomide / Q000008:administration & dosage* / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D054079:Vascular Malformations / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D033921:Vesicular Transport Proteins / Q000378:metabolism; D015027:Zebrafish; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D020533:Angiogenesis Inhibitors; D051792:Basic Helix-Loop-Helix Proteins; D002135:Calcium-Binding Proteins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D036341:Intercellular Signaling Peptides and Proteins; D051881:Receptor, Notch1; D013792:Thalidomide; D042461:Vascular Endothelial Growth Factor A; D033921:Vesicular Transport Proteins; D000099162:Endothelial PAS Domain-Containing Protein 1; C424126:DLL4 protein, human; C497442:HIF1A protein, human; C497761:NOTCH1 protein, human; C467484:VEGFA protein, human; C555023:VPS51 protein, human