Alterered Placental Function of 11β-HSD2 Knockout Mice

Fetal glucocorticoid exposure is a key mechanism proposed to underlie prenatal “programming” of adult cardiometabolic and neuropsychiatric disorders. Regulation of fetal glucocorticoid exposure is achieved by the placental glucocorticoid “barrier,” which involves glucocorticoid inactivation within the labyrinth zone of the murine placenta by 11 s -hydroxysteroid dehydrogenase 2 (11s-HSD2). Thus, the absence of placental 11s -HSD2 may impact on fetal and placental development. The current study investigated transport of amino acids and glucose, key factors required or fetal growth, and vascular development in placentas from 11s-HSD2+/+, +/-, and -/- fetuses derived from 11s-HSD2+/- matings. At embryonic day 15 (E15) (term E19), 11s-HSD2-/- fetal weight was maintained in comparison to 11s-HSD2+/+ fetuses. The maintenance of 11s-HSD2-/- fetal weight occurred despite a reduction in placental weight, suggesting that compensatory changes occur in the placenta to maintain function. However, by E18, 11s-HSD2-/- fetal and placental weights were both reduced. Transport studies revealed up-regulation of placental amino acid transport to 11s-HSD2-/- offspring at E15, coinciding with an increase in the expression of the amino acid transporters. Furthermore, at E18, placental glucose transport to 11s-HSD2-/- offspring was markedly reduced, correlating with lower fetal weight and a decrease in glucose transporter 3 expression. Stereological analyses of the labyrinth zone of the placenta revealed that the reduction in placental weight at E18 was associated with restriction of the normal increase in fetal vessel density over the final third of pregnancy. Our data suggest that restriction of fetal growth in 11s-HSD2-/- mice is mediated, at least in part, via altered placental transport of nutrients and reduction in placental vascularization.