Glucocorticoids, 11β-Hydroxysteroid Dehydrogenase: Mother, Fetus, or Both?

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 ß -hydroxysteroid dehydrogenase 2 (11ß-HSD2). Thus, the absence of placental 11ß -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 11ß-HSD2+/+, +/-, and -/- fetuses derived from 11ß-HSD2+/- matings. At embryonic day 15 (E15) (term E19), 11ß-HSD2-/- fetal weight was maintained in comparison to 11ß-HSD2+/+ fetuses. The maintenance of 11ß-HSD2-/- fetal weight occurred despite a reduction in placental weight, suggesting that compensatory changes occur in the placenta to maintain function. However, by E18, 11ß-HSD2-/- fetal and placental weights were both reduced. Transport studies revealed up-regulation of placental amino acid transport to 11ß-HSD2-/- offspring at E15, coinciding with an increase in the expression of the amino acid transporters. Furthermore, at E18, placental glucose transport to 11ß-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 11ß-HSD2-/- mice is mediated, at least in part, via altered placental transport of nutrients and reduction in placental vascularization.