Fetal glucocorticoid exposure is a key mechanism involved in adverse programming outcomes in the adult, including hypertension, anxiety and insulin resistance. While glucocorticoids may exert their effects directly on the fetus, they may also affect fetal growth through indirect effects on placental function. Regulation of fetal glucococorticoid exposure is achieved by the placental glucocorticoid barrier, which involves glucocorticoid inactivation within the labyrinth zone of the murine placenta by 11β-HSD2. Thus, absence of placental 11β-HSD2 may impact on fetal and placental development. The current study investigated vascular development and transport of amino acids and glucose, key factors required for fetal growth, in placentas from 11β-HSD2+/+,+/− and −/− fetuses derived from 11β-HSD2+/− matings. At E15 (term=E19), just before 11β-HSD2 levels drop in the +/+ placenta, 11β-HSD2−/− fetal weight was maintained in comparison to 11β-HSD2+/+ fetuses. This maintenance of 11β-HSD2−/− fetal weight was despite a reduction (11%) in placental weight. By E18 however, 11β-HSD2−/− fetal and placental weights were both reduced (16 and 7% respectively). Stereological analyses of the labyrinth zone of the placenta revealed that the reduction in placental weight at E18 was associated with impairment of the normal increase in fetal vessel density over the final third of pregnancy, with no effect on the density of maternal blood spaces. Transport studies revealed a compensatory upregulation of placental amino acid transport (44%) to 11β-HSD2−/− offspring at E15 but no alteration in glucose transport. Furthermore at E18, placental glucose transport to 11β-HSD2−/− offspring was markedly reduced (46%), correlating with lower fetal weight, whilst amino acid transport was not affected. 11β-HSD2−/− fetal plasma glucose levels at E18 were also decreased (42%), reflecting diminished placental glucose transport. Our data suggest that restriction of fetal growth in 11β-HSD2−/− mice is mediated, in part, via reduction in placental vascularisation and altered placental transport of nutrients.
|Publication status||Published - Apr 2008|