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ROS against preeclampsia
Preeclampsia is the onset of high blood pressure and proteinuria that acutely develops after about 20 weeks of pregnancy, which impairs fetal growth and can result in maternal organ damage. There are few treatment options available. Oxidative stress mediated by reactive oxygen species (ROS) has been proposed to inhibit blood vessel formation (a process called angiogenesis) in the placenta, which would be expected to increase the risk of preeclampsia; however, clinical trials have found antioxidants to be ineffective in preventing preeclampsia. Nezu et al. used a mouse model of preeclampsia in which the antioxidant system Nrf2 had been genetically or pharmacologically manipulated. Unexpectedly, genetic ablation of an inhibitor of Nrf2 or treatment with an activator of Nrf2 decreased placental angiogenesis, suppressed fetal growth, and worsened maternal survival. In contrast, deficiency of Nrf2 increased placental angiogenesis and improved fetal and maternal outcomes. These results indicate that ROS are necessary for the placental angiogenesis that reduces the risk of preeclampsia, and help to explain the negative results of the clinical trials of antioxidants.
Placental activation of the renin-angiotensin system (RAS) plays a key role in the pathogenesis of preeclampsia. Reactive oxygen species (ROS) are thought to affect placental angiogenesis, which is critical for preventing preeclampsia pathology. We examined the role of ROS in preeclampsia by genetically modifying the Keap1-Nrf2 pathway, a cellular antioxidant defense system, in a mouse model of RAS-induced preeclampsia. Nrf2 deficiency would be expected to impair cellular antioxidant responses; however, Nrf2 deficiency in preeclamptic mice improved maternal and fetal survival, ameliorated intra-uterine growth retardation, and augmented oxidative DNA damage. Furthermore, the placentas of Nrf2-deficient mice had increased endothelial cell proliferation with dense vascular networks. In contrast, the placentas of preeclamptic mice with overactive Nrf2 showed repressed angiogenesis, which was associated with decreased expression of genes encoding angiogenic chemokines and cytokines. Our findings support the notion that ROS-mediated signaling is essential for maintaining placental angiogenesis in preeclampsia and may provide mechanistic insight into the negative results of clinical trials for antioxidants in preeclampsia.