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 1 alpha (Hif-1 alpha). 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-1a. 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-1a, 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. CONCLUSION: Ang2, Notch1, Dll4 and Hif-1a may play an important role in the pathogenesis of GIVM and may be potential targets of thalidomide in the treatment of the disease.