Chronic Tempol Prevents Hypertension, Proteinuria, and Poor Feto-Placental Outcomes in BPH/5 Mouse Model of Preeclampsia

Abstract

Abstract-Recently we described a mouse model, BPH/5, that spontaneously develops the hallmark clinical features of preeclampsia. BPH/5 exhibit impaired placentation before the onset of hypertension and proteinuria, supporting a causal role for the placenta in the pathogenesis of preeclampsia. Here we tested the hypothesis that an increase in reactive oxygen species (ROS) early in pregnancy results in placental abnormalities leading to the maternal symptoms of preeclampsia. We further hypothesized that chronic antioxidant therapy would ameliorate both feto-placental abnormalities and maternal symptoms. ROS levels measured by dihydroethidium revealed significant increases in oxidative stress in BPH/5 placentas at midgestation compared with C57 controls. This increase in ROS was correlated with reduced expression and activity of cytoplasmic superoxide dismutase in early and midgestation BPH/5 placentas. These abnormalities in placental oxidant factors occurred before the onset of maternal symptoms, suggesting a possible causal link between increased ROS and maternal and feto-placental pathology in this model. In support of this, chronic treatment of BPH/5 with the superoxide dismutase-mimetic Tempol throughout gestation significantly improved fetal growth and survival. Furthermore, Tempol ameliorated pregnancy-induced increases in blood pressure and proteinuria in BPH/5 mothers. We confirmed that Tempol radical was present in plasma, and it normalized ROS levels in all placental zones in BPH/5. These data for the first time demonstrate an important causative role for increased ROS in the placenta in the pathogenesis of preeclampsia in a model that spontaneously develops the disease. The results also strongly suggest the potential utility of antioxidant therapy in treating preeclampsia. (Hypertension. 2008;51:1058-1065.)

An increased population of regulatory T cells improves the pathophysiology of placental ischemia in a rat model of preeclampsia

“…Placental oxidative stress has been shown to be increased in preeclamptic women, and placental and renal oxidative stress is observed in preclinical models preeclampsia, and it is implicated in contributing to the development of vascular dysfunction, proteinuria, and hypertension during pregnancy (9,13,27,28). Importantly reactive oxygen species (ROS) is a byproduct of inflammation and is elevated in response to RUPP CD4ϩ T cells and IL-17-and AT 1 -AA-induced hypertension during pregnancy.…”

Murine prolylcarboxypeptidase depletion induces vascular dysfunction with hypertension and faster arterial thrombosis

“…19 Confocal images were analyzed by morphometric analysis of pixels per nucleus using MetaMorph software Version 7 (Molecular Devices). The color threshold was set the same for each image, and the red pixel density was obtained by dividing the total pixel density value by the number of nuclei in the smooth muscle and endothelial layers or renal cortex.…”

Spiral Arterial Remodeling Is Not Essential for Normal Blood Pressure Regulation in Pregnant Mice

“…Gestational hemodynamic data from radiotelemetric studies have been reported for normal rats 28,29 and normal B6 mice, 30,31 but none of these publications provide fully characterized hemodynamic profiles for normal animals, particularly using continuous radiotelemetry. Nishizawa et al 32 compared SAP and DAP using indirect tail-cuff measures between syngenically (B6ϫB6) and allogeneically mated (B6ϫBALB/c) mice from gd7 to gd17.…”