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

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.

Wild-Type Male Offspring of fmr-1+/− Mothers Exhibit Characteristics of the Fragile X Phenotype

“…Some other studies reported maternal genotype effects on offspring behavior. Lack of several proteins and hormones, including adrenomedullin, have been shown to alter maternal physiology and consequently offspring behavior (Li et al, 2006). In another report, variability in maternal care (Francis and Meaney, 1999) was demonstrated to alter the level of anxiety in the offspring via an epigenetic regulation of the glucocorticoid receptor (Weaver et al, 2004).…”

Mice heterozygous for adrenomedullin exhibit a more extreme inflammatory response to endotoxin-induced septic shock

“…Adult female mice heterozygous for AM display profound reproductive defects [16] and are protected from hypertension-induced cardiovascular end organ damage [2]. Otherwise, adult male and female AM heterozygous mice are born at the expected Mendelian ratios, survive to adulthood and have normal blood pressures under basal and stressed conditions with no obvious phenotypic defects.…”

Adrenomedullin and endocrine control of immune cells during pregnancy

“…[18][19][20][21][22][23][24] For example, just prior to implantation in mice, Adm is highly expressed in the trophectoderm cells of the early blastocyst and the luminal epithelial cells of the uterine lining. 20,25,26 Shortly after implantation, and during the rapid expansion of the murine decidua, Adm expression is strongly centered within the primary decidual zone, a 3-5 cell-layer thick region surrounding the recently implanted embryo which serves as a temporary and physical barrier to immunological attack. 26 However, Adm expression is most enriched in mouse trophoblast giant cells (TGCs) throughout pregnancy, with approximately 30-fold higher levels in differentiated TGCs compared to undifferentiated precursors.…”

“…20,25,26 Shortly after implantation, and during the rapid expansion of the murine decidua, Adm expression is strongly centered within the primary decidual zone, a 3-5 cell-layer thick region surrounding the recently implanted embryo which serves as a temporary and physical barrier to immunological attack. 26 However, Adm expression is most enriched in mouse trophoblast giant cells (TGCs) throughout pregnancy, with approximately 30-fold higher levels in differentiated TGCs compared to undifferentiated precursors. 26 Because TGCs are active players in the processes of decidualization, implantation and placentation, this robust expression of Adm from these fetal cells implicates AM in many stages of pregnancy.…”

“…26 However, Adm expression is most enriched in mouse trophoblast giant cells (TGCs) throughout pregnancy, with approximately 30-fold higher levels in differentiated TGCs compared to undifferentiated precursors. 26 Because TGCs are active players in the processes of decidualization, implantation and placentation, this robust expression of Adm from these fetal cells implicates AM in many stages of pregnancy. 27 Moreover, TGCs of Adm 2/2 placentas undergo apoptosis, further suggesting that AM is critical for the survival of these cells that are central to the maintenance of a healthy pregnancy.…”