Fetal glucocorticoid exposure is a key mechanism involved in adverse
programming outcomes in the adult. Impairment of fetal growth has predominantly been
attributed to direct effects of glucocorticoids on the fetus, however
glucocorticoid-mediated fetal growth retardation is likely also to relate to
disturbances in placental growth and function. 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 11b-hydroxysteroid dehydrogenase
type 2 (11β-HSD2). A global
knockout of 11β-HSD2 in the mouse has a dramatic effect on the placenta with
absence of 11β-HSD2 (11β-HSD2-/-) alteringplacental nutrient
transport (namely glucose and amino acids) in comparison to wildtype placentas.
This altered placental function is associated with reduced capillary networks
and accompanying declines in angiogenic factors. Furthermore, the compromisedplacental vascular development of 11β-HSD2-/- fetuses is associated
with compromised placental and umbilical cord haemodynamics, as assessed by
high resolution ultrasound. In addition, measures of cardiac function by
ultrasound revealed 11β-HSD2-/- fetal heart function to be
impaired.
Interestingly, administration of pravastatin (which is known to result in
marked restoration of placental vasculogenesis in mouse models of preeclampsia)
throughout gestation increases placental weight and ameliorates the aberrant
umbilical and placental cord flow of 11β-HSD2-/-fetuses. Fetal weight and cardiac parameters
of 11β-HSD2-/-fetuses are also partially normalised
due to pravastatin treatment. This work
highlights the potential for the placenta to be
viewed as a therapeutic target to improve fetal health outcomes. It also
reinforces that adverse
programming effects of glucocorticoids are not exclusively due to direct
actions on the fetus but also a consequence of changes in placental development
and function.