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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 3

Abnormal implantation spacing in AM+/–females.

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Abnormal implantation spacing in AM+/–females.
               
(A) Timed...
(A) Timed natural matings or blastocyst transfers were performed in wild-type (white bars) and AM+/– female mice (gray bars). The number of implanted embryos was determined between gestational stages E5.5 and E8.5. The number at the bottom of the bars represents the number of litters examined for each cross. (B) Evans blue dye injections of pregnant wild-type and AM+/– female mice at gestational stages E4.5 and E5.5 revealed comparable conceptus sizes, demonstrating that timing of implantation was conserved in AM+/– female mice. However, AM+/– female mice displayed abnormal spacing of and overcrowded conceptuses in the uterine horn (arrowheads) compared with wild-type control females.

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

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