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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 6

Fetal AM gene expression is upregulated in invasive TGCs.

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Fetal AM gene expression is upregulated in invasive TGCs.
              ...
(A) Fluorescence microscopy of preimplanting blastocysts generated from an AM+/– intercross and flushed from the uterine horn of an AM+/– female at E3.5. Note the strong fluorescence present in both mural and polar trophectoderm cells and a fainter signal in the inner cell mass. The left blastocyst is AM–/– and has approximately twice the intensity of fluorescence as the right AM+/– blastocyst. (B) Confirmation of TGC differentiation in a TS cell line using Hand1 and proliferin gene expression markers. Results from the quantitative RT-PCR experiment show the fold change in gene expression in differentiated TGCs compared with that in the undifferentiated TS cell culture, which was arbitrarily set at 1. (C) Quantitative measurement of AM gene expression in differentiated TGCs compared with that in the undifferentiated TS cell culture. All data were normalized to a GAPDH internal control. **P < 0.001 compared with undifferentiated TS cells.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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