25-OR]: Induction of Nrf2-dependent heme oxygenase-1 promotes angiogenesis in human umbilical vein endothelial cells

Nrf2 is a potent transcription factor that regulates the transcription of a multiple antioxidative-genes. We reported that Nrf2-dependent redox signaling contributes to impaired invasion of the extravillous trophoblast in early onset IUGR associated with preeclampsia. Recent discussion about evidence of a link between Nrf2 and vascular the vascular endothelial growth factor has focused on its downstream target protein, heme oxygenase-1 (HO-1). HO-1 metabolizes heme to biliverdin, iron and carbon monoxide (CO). To assess the interaction between Nrf2 signaling and the angiogenic process, we examined in vitro the effect of Nrf2 activation on the expression of pro- and anti-angiogenic factors, VEGF and the soluble fms-like tyrosine kinase-1 (sFlt-1).The angiogenic effect of Nrf2 activation was tested using BeWo and the primary human umbilical vein endothelial cells (HUVECs). ELISA, scratch- and tube formation-assays were mainly applied in this study. HUVECs migration and tube formation assays were performed in the presence or absence of sulforaphane, a potent inducer of Nrf2 signaling.The activation of HO-1 via Nrf2 led to a significant increase in the protein levels of VEGF and decrease in the augmented-sFlt-1 in the supernatant of the treated cells. Up-regulation of HO-1/CO enhanced tube formation and migration of the endothelial cells. And the knock down of Nrf2 expression in the aforementioned cells reduced the angiogenic potential of sulforaphane.Our data revealed that the activation of the Nrf2 and its target protein HO-1 induced the expression of VEGF in vitro and exerted positive effects on endothelial functions. We could further demonstrate that the release of sFlt-1 has been reduced after treatment with Nrf2 inducer, sulforaphane. Thus Nrf2 activation during pregnancy may improve the imbalance between the pro-and anti-angiogenic factors mainly described in preeclampsia.N. Kweider: None. J. Lambertz: None. T. Goecke: None. A. Ludwig: None. T. Pufe: None. C.J. Wruck: None. W. Rath: None.