HIF-1α and HIF-2α induced angiogenesis in gastrointestinal vascular malformation and reversed by thalidomide

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