Altered placental function of 11beta-hydroxysteroid dehydrogenase 2 knockout mice

Abstract

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

Figure 1

Changes in placental transport of ¹⁴C-MeAIB and ¹⁴C-glucose in 11ß-HSD2^+/+, ^+/- and ^-/- fetuses at E15 and E18 expressed per gram of placenta (A and C respectively) or per gram of fetus (B and D respectively). Values are the mean + SEM. ^✤ denotes an overall effect of gestational age (two-way ANOVA, P<.05), * denotes differences from 11ß-HSD2^+/+ within the time point (one-way ANOVA, P<0.05).

Figure 2

Relative mRNA expression of the System A amino acid transporters Slc38a1 (A), Slc38a2 (B) and Slc38a4 (C) in the labyrinth zone of placentas from 11ß-HSD2^+/+, ^+/- and ^-/- fetuses at E15 and E18. Values are the mean + SEM. ^✤ denotes an overall effect of gestational age (two-way ANOVA, P<0.05), * denotes differences from 11ß-HSD2^+/+ within the time point (one-way ANOVA, P<0.05).

Figure 3

Relative mRNA expression of the glucose transporters Slc2a1 (A) and Slc2a3 (B) in the labyrinth zone of placentas from 11ß-HSD2^+/+, ^+/- and ^-/- fetuses at E15 and E18. Values are the mean + SEM. ^✤ denotes an overall effect of gestational age (two-way ANOVA, P<0.05), * denotes differences from 11ß-HSD2^+/+ within the time point (one-way ANOVA, P<0.05).

Figure 4

Relative expression of Vegf-a (A) and Pparγ (B) mRNAs in the labyrinth zone of placentas from 11ß-HSD2^+/+, ^+/- and ^-/- fetuses at E15 and E18. Values are the mean + SEM. ^✤ denotes an overall effect of gestational age (two-way ANOVA, P<0.05), * denotes differences from 11ß-HSD2^+/+ within the time point (one-way ANOVA, P<0.05).