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Reduced maternal expression of adrenomedullin disrupts fertility, placentation, and fetal growth in mice
Manyu Li, … , Oliver Smithies, Kathleen M. Caron
Manyu Li, … , Oliver Smithies, Kathleen M. Caron
Published October 2, 2006
Citation Information: J Clin Invest. 2006;116(10):2653-2662. https://doi.org/10.1172/JCI28462.
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Research Article Reproductive biology

Reduced maternal expression of adrenomedullin disrupts fertility, placentation, and fetal growth in mice

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Abstract

Adrenomedullin (AM) is a multifunctional peptide vasodilator that is essential for life. Plasma AM expression dramatically increases during pregnancy, and alterations in its levels are associated with complications of pregnancy including fetal growth restriction (FGR) and preeclampsia. Using AM+/– female mice with genetically reduced AM expression, we demonstrate that fetal growth and placental development are seriously compromised by this modest decrease in expression. AM+/– female mice had reduced fertility characterized by FGR. The incidence of FGR was also influenced by the genotype of the embryo, since AM–/– embryos were more often affected than either AM+/– or AM+/+ embryos. We demonstrate that fetal trophoblast cells and the maternal uterine wall have coordinated and localized increases in AM gene expression at the time of implantation. Placentas from growth-restricted embryos showed defects in trophoblast cell invasion, similar to defects that underlie human preeclampsia and placenta accreta. Our data provide a genetic in vivo model to implicate both maternal and, to a lesser extent, embryonic levels of AM in the processes of implantation, placentation, and subsequent fetal growth. This study provides the first genetic evidence to our knowledge to suggest that a modest reduction in human AM expression during pregnancy may have an unfavorable impact on reproduction.

Authors

Manyu Li, Della Yee, Terry R. Magnuson, Oliver Smithies, Kathleen M. Caron

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Figure 8

Effects of maternal and fetal depletion of AM in pregnancy.

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Effects of maternal and fetal depletion of AM in pregnancy.
In wild-type...
In wild-type mice (Normal), AM gene expression is highly and coordinately upregulated in the maternal uterine luminal epithelium and surrounding stroma as well as fetal trophectoderm cells at the time of implantation. Due to effective gene targeting of the AM gene, AM peptide secretion is reduced by 50% in the uterine wall of heterozygote females. This modest genetic reduction results in abnormal implantation spacing, morphological defects in placentation, FGR, and subsequent reduced fertility. Implanting blastocysts from AM+/– intercrosses can be of 3 genotypes, AM+/+, AM+/–, or AM–/–, and thus they contribute different amounts of AM peptide to the implantation site: 100%, 50%, or 0% of normal, respectively. Thus, the combined effects of maternal and fetal depletion of AM result in reduced and varying concentrations of AM peptide at the implantation site. While heterozygous loss of fetal AM does not significantly affect the incidence of FGR, a greater incidence of FGR is significantly associated with AM–/–embryos, suggesting an essential function for the peptide during early embryonic development. ICM, inner cell mass.
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