Superoxide scavenging improves early placental development and fetal growth and survival in a mouse model of pre‐eclampsia (PE)

Abstract

We have described a mouse model of PE (BPH5) that exhibits impaired placentation prior to onset of hypertension and proteinuria. The mechanisms of placental dysfunction in BPH5 are not known. Initial studies showed that CuZnSOD activity is reduced by half in mid-gestation BPH5 placenta compared to controls (32.2±3.3 U/mg protein BPH5 vs 61.6±2.2 C57, p<0.05, n=5). Early gestation treatment of BPH5 mice with the SOD mimic Tempol (1mM in drinking water) prevented late-gestational hypertension and proteinuria. Here we hypothesized that amelioration of PE in BPH5 occurred because Tempol restored the oxidative balance in placenta. EPR studies showed significant levels of Tempol in placenta of treated BPH5 (83.7±65.9 peak height/mg protein, n=6), whereas it was undetectable in controls. Early survival of implanted conceptuses was significantly improved from 61.9±4.2% (n=23) in untreated BPH5 to 84.9±3.2% (n=47, p<0.05) in Tempol-treated BPH5. Tempol also normalized media:lumen ratios of decidual arteries in placental sections (2.47±0.3 BPH5, 1.69±0.2 BPH5 + Tempol, 1.34±0.2 C57, n=14–23, p<0.05), and this was associatedwith increases in mid-gestation placental weights (66.0±4.5 mg BPH5 vs. 95.5±6.5 BPH5 + Tempol, n=46 & 28, p<0.05). These placental changes were paralleled by normalization of term fetal weight. These results demonstrate oxidative stress plays a key role in abnormal placentation in PE, and O2.- scavenging starting early in gestation normalizes feto-placental outcomes. AHA #0510021Z