The roles of the placenta and oxidative stress in the pathogenesis of pre-eclampsia in a novel genetic mouse model

Pre-eclampsia is a very serious disease of pregnancy that is surprisingly common. In spite of its prevalence and potentially devastating consequences, little is known about the pathophysiology of pre-eclampsia, in part due to the lack of animal models which develop the disease spontaneously. We hypothesized that BPH/5, an inbred mouse strain with mildly elevated basal blood pressure would develop pre-eclampsia in pregnancy, because modest elevations in blood pressure prior to pregnancy strongly predispose women toward the development of pre-eclampsia. We discovered that BPH/5 show the diagnostic criteria of pre-eclampsia, hypertension and proteinuria in late pregnancy, and exhibit poor fetal outcomes, another hallmark of pre-eclampsia in women. In light of the two-stage model of pre-eclampsia, which suggests that the placenta is the source of the disease, we hypothesized BPH/5 placentas would exhibit developmental abnormalities prior to the onset of maternal symptoms. In fact placentas of BPH/5 do exhibit severe histomorphic changes in parallel with marked dysregulation of key trophoblast genes and genes related to lipid metabolism and oxidative stress. Because of these findings, and emerging evidence from the clinical literature showing a role for reactive oxygen species (ROS) in pre-eclampsia, we hypothesized that placental dysfunction in BPH/5 was due to increased oxidative stress in the placenta. We discovered that a key antioxidant enzyme is deficient in BPH/5 placenta which is associated with increased placental ROS. To establish a causal role for oxidative stress in this model, BPH/5 were treated with the antioxidant Tempol. Treatment of BPH/5 with Tempol completely abolished late-gestational maternal symptoms and significantly improved feto-placental outcomes. In addition to a role for oxidative stress in the placenta, studies in isolated mesenteric vessels showed that increased ROS also leads to maternal vascular dysfunction. Finally, uterine transfer of BPH/5 embryos into C57 surrogates demonstrated that poor placental development was the product of feto-placental genetics and not the cardiovascular phenotype of the mother. Collectively, these studies provide new insights into the role of the placenta in pre-eclampsia and show a causal role for ROS in the pathogenesis of the disease.