Dihydroartemisinin enhances VEGFR1 expression through up-regulation of ETS-1 transcription factor.

Angiogenesis is required for tumor growth. Dihydroartemisinin (DHA), a the effective anti-malarial derivative of artemisinin, demonstrated potent anti-angiogenic activities that closely related to the regulation of vascular endothelial growth factor (VEGF) signaling cascade. VEGF receptor 1 (VEGFR1), a receptor in endothelial cells (ECs), coordinately regulate angiogenic activity triggered by ligand-receptor binding. Here we aimed to explore the effects of DHA on VEGFR1 expression in ECs. We found that DHA significantly increases VEGFR1 expression in human umbilical vein endothelial cells (HUVECs). In addition, DHA significantly upregulates the level of V-Ets Avian Erythroblastosis Virus E26 Oncogene Homolog 1 (ETS-1), a transcriptional factor which binds to the human VEGFR1 promoter. ChIP assay showed that DHA increases ETS-1 binding to the -52 ETS motif on the VEGFR1 promoter. Knockdown of ETS-1 by RNA interference abolished DHA-induced increase of VEGFR1 expression. Taken together, we demonstrated that DHA elevates VEGFR1 expression via up-regulation of ETS-1 transcription in HUVECs.