Abstract 094: Cox2 Inhibition During Decidualization Improves Fetal Growth Restriction In The BPH/5 Mouse Model Of Preeclampsia

Abstract

Preeclampsia (PE) presents as maternal hypertension and proteinuria during the second half of pregnancy and often results in preterm delivery of a growth restricted baby. Despite being a leading cause of perinatal and maternal morbidity/mortality, the underlying mechanism(s) is unknown. Because signs resolve upon delivery of the placenta, abnormal placentation is widely accepted as the cause of PE. BPH/5 mice spontaneously develop the cardinal features of PE along with poor fetoplacental outcomes, such as fetal growth restriction. We have shown that BPH/5 implantation sites exhibit significant up-regulation of Ptgs2 (the gene encoding Cox2) at e7.5 as compared to C57. Since Cox2 and Cox2-derived prostaglandins (PGs) are crucial for uterine decidualization and placental angiogenesis, we tested the hypothesis that BPH/5 mice have dysregulated PG synthesis during decidualization and that this contributes to poor fetoplacental outcomes. Because e7.5 is considered the peak of decidualization, we designed experiments to selectively target Cox2 at this time in BPH/5 implantation sites. Administration of celecoxib by oral gavage at e6.5 (10mg/kg BW) caused a 2-fold reduction in Cox2 protein expression in BPH/5 implantation sites at e7.5 (n=3-4; p<0.05 vs BPH/5 veh). This had no effect on Cox2 levels in C57. This was associated with a significant reduction in PGE 2 synthesis (51.6±17.3 vs veh: 135.6±49.7 pg/mg), but not PGI 2 in e7.5 BPH/5 implantation sites (n=4-5; p<0.05). Neither PGE 2 nor PGI 2 synthesis was altered in C57 implantation sites. Furthermore, celecoxib improved fetal growth restriction in BPH/5 pups at e18.5 (1.108±0.091 vs veh: 1.036±0.021g), which was associated with an increase in placental weight (99.7±1.6 vs veh: 91.32±2.2mg) in BPH/5 females (n=20-38; p<0.05). These results provide evidence that Cox2 and PGE 2 play a key role in fetoplacental development in a mouse model of PE, and that celecoxib improves fetal outcomes in BPH/5 females. This highlights the significance of proper decidual angiogenesis and suggests that aberrations in these processes in early pregnancy may contribute to fetal growth restriction seen in PE pregnancies.