Pre-eclampsia (PE) is a pregnancy-specific disease resulting in systemic maternal endothelial dysfunction, associated with placental hypoperfusion and increased generation of reactive oxygen species (ROS) and pro-inflammatory mediators (Noris, 2005). We previously identified phenotypic alterations in human umbilical vein endothelial cells (HUVEC) isolated from PE pregnancies (Steinert et al., 2002; Afzal-Ahmed et al., 2007). In the present study, we examined whether PE affects activation of the redox sensitive transcription factor Nrf2 and whether changes in oxygen tension (21% versus 5%) affect Nrf2 mediated HO-1 protein expression in normal and PE HUVEC. Normal and PE HUVEC were cultured in M199 + 20% serum. Nrf2 nuclear accumulation was assessed in cells stimulated for 1-4 h with 20µM 4-hydroxynonenal (HNE, lipid peroxidation product raised in PE). Cells were also adapted to 5% or 21% O2, treated for 4-24h with 10-40µM HNE and HO-1 expression determined by immunoblotting. HNE increased nuclear accumulation of Nrf2 which were not altered significantly in PE cells. HNE increased HO-1 expression in normal HUVEC (>2-fold), which was significantly attenuated in PE cells. HNE induced HO-1 expression was less pronounced in normal or PE HUVEC adapted to 5% O2. Our findings suggest that fetal endothelial cells from PE pregnancies may be more susceptible to oxidative damage as a result of impaired antioxidant enzyme expression and/or activity. As alterations in antioxidant gene expression in PE HUVEC persist in culture, it seems likely that the fetal vasculature is affected by increased ROS production in PE, leading potentially to fetal programming of cardiovascular disease in adulthood (Vatten et al., 2003; Tenhola et al., 2006).