P357Nrf2 sequesters Keap1 preventing endothelial dysfunction

JNK were not causally linked to the upregulation of Flt1 and Angpt2.We demonstrated that PKCinduced transcription of Angpt2 and Flt1 involved the transcription factor Ets1, as a combined knockdown of Fzd5 and Ets1 completely blocked the enhanced Angpt2 expression, and reduced the upregulation of Flt1 by almost 50% (both n¼4, P<0.05).In addition, an intervention with knockdown of Ets1 on top of the Fzd5 knockdown also partially rescued the poor angiogenic phenotype observed in the 3D co-culture model (n¼6, P<0.05), indicating that this transcription factor was critically involved in suppressing angiogenesis in absence of Fzd5.Conclusions: The current study provides evidence for a pro-angiogenic role of Fzd5, which was shown to be involved in endothelial tubule formation, cell cycle progression and migration, and does so by repression of PKC/Ets1-mediated transcription of Flt1 and Angpt2.