Abstract 287: Evidence For Increased Autophagy In Fetoplacental Units Of Bph/5, A Mouse Model Of Pre-eclampsia (PE)

Abstract

Autophagy, a mechanism of cell survival during times of stress, plays an important role in normal placentation, protecting the fetus during fluctuations in conditions such as nutrient availability. In cases of placental insufficiency, often present in PE, autophagy may be defective. We have shown that BPH/5 mice, in addition to spontaneously developing a PE-like syndrome including late-gestational hypertension and proteinuria, exhibit abnormal placentation and poor feto-placental outcomes. Here we tested the hypothesis that there is increased autophagy in fetoplacental units (FPUs) of pregnant BPH/5 females. RNA was extracted from FPUs (e10.5) of BPH/5 and C57 control mice and analyzed for biomarkers of autophagy. BPH/5 showed a significant increase in both Beclin-1 and LC3-β compared to C57 (1.5-fold for each, n=7; p<0.05). Increased autophagy in e10.5 BPH/5 FPUs was corroborated at the protein level using ELISA to measure Beclin-1 (0.6±0.1 control vs. 2±0.17 ng/mL BPH/5; n=7; p<0.05). We also analyzed protein levels of p62, an autophagy biomarker which is degraded during autophagy. Consistent with these other findings, the levels of p62 were lower in BPH/5 mice (29.7±2.5 controls vs. 7.2±1.3 ng/mL BPH/5, p<0.05). Given that autophagy in trophoblasts plays a key role in the invasion of these cells and thus remodeling of uterine arteries, we examined the invasion capacity of e10.5 trophoblasts isolated from C57 and BPH/5 mice. Trophoblasts from BPH/5 mice were much less invasive when compared to C57 (2-fold decrease, n=7; p<0.05). Inhibition of autophagy with chloroquine diphosphate (50 μM) significantly improved invasion capacity of these cells (1.6-fold increase; n=7; p<0.05). Collectively, these data demonstrate that autophagy is defective in FPUs from BPH/5 mice, and suggest that this may play a causal role in PE in this model.