Thalidomide-induced angiopoietin 2, Notch1 and Dll4 downregulation under hypoxic condition in tissues with gastrointestinal vascular malformation and human umbilical vein endothelial cells.
OBJECTIVE
To determine the pathogenesis of gastrointestinal vascular malformation (GIVM) and the mechanism of thalidomide in treating GIVM by evaluating the expression of angiopoietin 2 (Ang2), Notch1, delta-like ligand 4 (Dll4) and hypoxia inducible factor 1α (Hif-1α).


METHODS
Data of 10 patients with histology-confirmed GIVM were reviewed. Immunohistochemistry of surgically resected GIVM tissues and the adjacent mucosa of the patients and normal tissues from those who had undergone colonoscopy for health examination was performed to examine the expressions of Ang2, Notch1, Dll4 and Hif-1α. In addition, in vitro effect of thalidomide on Ang2, Notch1 and Dll4 in human umbilical vein endothelial cells (HUVEC) and on HUVEC proliferation was also investigated during normoxic and hypoxic conditions.


RESULTS
GIVM lesions presented as tortuous, dilated arterioles, venules and capillaries. Ang2, Notch1 and Dll4 showed strong immunoreactivity in the cytoplasm and nuclei of GIVM lesions but negative or weak positivity in the intestinal mucosa of the adjacent tissues and normal mucosa. Under hypoxic condition the expressions of Hif-1α, Ang2, Notch1 and Dll4 were upregulated and the tube formation was more abundant with a greater diameter of tubes. Moreover, thalidomide downregulated their expression in HUVEC and HUVEC proliferation decreased in a concentration-dependent manner under both hypoxic and normoxic conditions.


CONCLUSIONS
Ang2, Notch1, Dll4 and Hif-1α may play an important role in the pathogenesis of GIVM and may be potential targets of thalidomide in the treatment of the disease.
Division of Gastroenterology and Hepatology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, Shanghai, China; Key Laboratory of Gastroenterology & Hepatology, Ministry of Health (Shanghai Jiao Tong University), Shanghai, China.
Qian
Q
Feng
Hong Hong
HH
Tan
Zhi Zheng
ZZ
Ge
Yun Jie
YJ
Gao
Hui Min
HM
Chen
Shu Dong
SD
Xiao
D000328:Adult; D000368:Aged; D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D042702:Angiopoietin-2 / Q000096:biosynthesis / Q000235:genetics; D002455:Cell Division / Q000187:drug effects; D015687:Cell Hypoxia / Q000502:physiology; D002478:Cells, Cultured; D015536:Down-Regulation / Q000187:drug effects; D005260:Female; D041981:Gastrointestinal Tract / Q000098:blood supply* / Q000378:metabolism; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000096:biosynthesis / Q000235:genetics; D008297:Male; D008565:Membrane Proteins / Q000096:biosynthesis / Q000235:genetics; D008875:Middle Aged; D012333:RNA, Messenger / Q000235:genetics; D051881:Receptor, Notch1 / Q000096:biosynthesis / Q000235:genetics; D012189:Retrospective Studies; D013792:Thalidomide / Q000494:pharmacology*; D054079:Vascular Malformations / Q000378:metabolism* / Q000473:pathology; D055815:Young Adult
C586513:ANGPT2 protein, human; D020533:Angiogenesis Inhibitors; D042702:Angiopoietin-2; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; C497761:NOTCH1 protein, human; D012333:RNA, Messenger; D051881:Receptor, Notch1; C064045:delta protein; D013792:Thalidomide
Dll4 protein; alpha subunit; angiopoietin; hypoxia-inducible factor 1; thalidomide; vascular malformation