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Decidual Cox2 inhibition improves fetal and maternal outcomes in a preeclampsia-like mouse model
Jenny L. Sones, … , Sudhansu K. Dey, Robin L. Davisson
Jenny L. Sones, … , Sudhansu K. Dey, Robin L. Davisson
Published March 17, 2016
Citation Information: JCI Insight. 2016;1(3):e75351. https://doi.org/10.1172/jci.insight.75351.
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Research Article Reproductive biology

Decidual Cox2 inhibition improves fetal and maternal outcomes in a preeclampsia-like mouse model

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Abstract

Preeclampsia (PE) is a disorder of pregnancy that manifests as late gestational maternal hypertension and proteinuria and can be life-threatening to both the mother and baby. It is believed that abnormal placentation is responsible for the cascade of events leading to the maternal syndrome. Embryo implantation is critical to establishing a healthy pregnancy. Defective implantation can cause adverse “ripple effects,” leading to abnormal decidualization and placentation, retarded fetal development, and poor pregnancy outcomes, such as PE and fetal growth restriction. The precise mechanism(s) of implantation defects that lead to PE remain elusive. BPH/5 mice, which spontaneously develop the cardinal features of PE, show peri-implantation defects including upregulation of Cox2 and IL-15 at the maternal-fetal interface. This was associated with decreased decidual natural killer (dNK) cells, which have important roles in establishing placental perfusion. Interestingly, a single administration of a Cox2 inhibitor (celecoxib) during decidualization restrained Cox2 and IL-15 expression, restored dNK cell numbers, improved fetal growth, and attenuated late gestational hypertension in BPH/5 female mice. This study provides evidence that decidual overexpression of Cox2 and IL-15 may trigger the adverse pregnancy outcomes reflected in the preeclamptic syndrome, underscoring the idea that Cox2 inhibitor treatment is an effective strategy for the prevention of PE-associated fetal and maternal morbidity and mortality.

Authors

Jenny L. Sones, Jeeyeon Cha, Ashley K. Woods, Amanda Bartos, Christa Y. Heyward, Heinrich E. Lob, Catherine E. Isroff, Scott D. Butler, Stephanie E. Shapiro, Sudhansu K. Dey, Robin L. Davisson

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Figure 1

BPH/5 female mice exhibit dysregulated peri-implantation events.

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BPH/5 female mice exhibit dysregulated peri-implantation events.
(A) Rep...
(A) Representative pontamine blue–stained implantation sites from C57 and BPH/5 mice (E5.5). Area of embryo clustering is bracketed. (B) Time course of implantation sites counted per litter in pregnant C57 and BPH/5 females during the peri-implantation period. n = 7–10. * P < 0.05 versus gestation-matched C57 females using a 2-way ANOVA. (C) Quantification of staged preimplantation embryos flushed from strain-matched (C57 × C57; BPH/5 × BPH/5) and reciprocal crosses of C57 females × BPH/5 males (C57 × BPH/5) and BPH/5 females × C57 males (BPH/5 × C57). n = 4–6 females; 40–50 embryos. * P < 0.05 versus C57 × C57 and † P < 0.05 versus C57 × BPH/5, by 1-way ANOVA. (D) Representative images of ALP-stained implantation sites harvested from C57 and BPH/5 females during the peri-implantation period. Scale bar: 500 μm. (E) Quantification of the area of decidualization (purple staining) represented as a ratio of the total implantation site area. n = 3–6 sections. * P < 0.05 versus gestation-matched C57 females, by 2-way ANOVA. Data represent the mean ± SEM. ALP, alkaline phosphatase.

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