Abstract 12: Cox2 Signaling During the Peri-implantation Period Plays an Important Role in Fetoplacental Heath in a Mouse Model of Preeclampsia, BPH/5

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Preeclampsia (PE), a hypertensive proteinuric disease of pregnancy, is a leading cause of perinatal and maternal morbidity/mortality. Although abnormal placentation is widely accepted as a cause for PE, the underlying mechanism is unclear. The BPH/5 mouse model spontaneously develops the cardinal features of PE with poor fetoplacental outcomes. These mice exhibit deferred implantation coincident with a delayed rise in serum estrogen and defective decidualization. We tested the hypothesis that aberrations in peri-implantation events influence fetoplacental health in BPH/5 mice. Real time PCR, in situ hybridization (ISH), and Western blotting were performed to characterize the expression of critical molecular mediators during the peri-implantation period in BPH/5 vs C57 control females. Implantation sites (IS) of BPH/5 females show reduced levels of Lif (2-fold), Bmp2 (8.5-fold) and Ptgs2 (encoding Cox2, 4-fold) on day 4.5 of pregnancy (n=6-9, p<0.05 vs C57). By day 5.5, Ptgs2 is upregulated in BPH/5 IS (2-fold; n=7, p<0.05 vs C57), which persists through day 7.5 and is consistent with upregulated Cox2 protein levels (2.75-fold±0.1; n=4, p<0.05 vs C57). ISH results are consistent with those of RT-PCR and demonstrated appropriate expression patterns of Lif, Bmp2, and Ptgs2. BPH/5 mice demonstrate three increasingly severe phenotypic classes of fetoplacental health as seen by ultrasound at day 10.5: healthy, compromised, and resorbed. Since Cox2-derived prostaglandins are crucial for decidualization, placentation and placental angiogenesis, we tested the effect of a selective Cox2 inhibitor (celecoxib) on fetoplacental development in BPH/5 females. Administration of celecoxib by oral gavage on day 6.5 (10mg/kg BW/dose) increased the percentage of healthy embryos (65.9±6.8 vs 45.1±7.9 veh) with reduced percentage of compromised embryos (20.7±2.5 vs 35.4±6.1veh) within BPH/5 litters (n=4-5, p<0.05). These results provide evidence that Cox2 plays a key role in fetoplacental health in a mouse model of PE, and that celecoxib improves fetoplacental outcomes in BPH/5 females. This highlights the significance of peri-implantation events in pregnancy outcome and suggests that aberrations in early pregnancy may give rise to PE.

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