HIF-1? and HIF-2? 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-1?) and 2 alpha (HIF-2?/EPAS1) are in the same family and act as master regulators of the adaptive response to hypoxia. HIF-1? and HIF-2? 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-1? and HIF-2? during angiogenesis and the mechanism of thalidomide action. In vitro experiments confirmed that vascular endothelial growth factor (VEGF) was a direct target of HIF-2? and that HIF-1? and HIF-2? regulated NOTCH1, Ang2, and DLL4, which enhanced vessel-forming of endothelial cells. Thalidomide down-regulated the expression of HIF-1? and HIF-2? and inhibited angiogenesis. In vivo zebrafish experiments suggested that HIF-2? 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-1? and HIF-2? expression, which further regulated downstream factors, including VEGF, NOTCH1, DLL4, and Ang2. The abnormally high expression of HIF-1? and HIF-2? may contribute to GIVM.

SUBMITTER: Feng N 

PROVIDER: S-EPMC4888746 | biostudies-literature | 2016 Jun

REPOSITORIES: biostudies-literature