Glucocorticoid excess in pregnancy impairs placental haemodynamics with novel implications for fetal cardiac function. (#17)
Fetal glucocorticoid exposure is a key mechanism involved in adverse programming outcomes in the adult. 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 11b-hydroxysteroid dehydrogenase type 2 (11β-HSD2). We have previously shown that global depletion of 11β-HSD2 has a dramatic effect on the placenta with absence of 11β-HSD2 compromisingplacental vascular development. This current study used high resolution ultrasound to assess umbilical cord flow and fetal cardiac function in heterozygous 11β-HSD2 matings at E14.5 and E17.5. Quantitative RT-PCR was conducted to assess markers of development and glucocorticoid exposure in fetal hearts. Umbilical vein flow in 11β-HSD2-/- fetuses did not undergo the normal gestational increase that occurs in wild-type littermates (P<0.05) and similarly, the resistance index in the umbilical artery did not undergo the normal gestational decline (P<0.001). The umbilical artery resistance index strongly correlated (r=-0.7577, P<0.0001) with an impairment of fetal cardiac function at E17.5, as the E/A wave ratio did not increase over gestation in 11β-HSD2-/- fetuses in comparison to wild-type littermates (P<0.001). The impaired cardiovascular function in the 11β-HSD2-/- fetuses is counter-intuitive as in the absence of 11β-HSD2, the fetal heart should be exposed to higher levels of glucocorticoids which is predicted to bring about a precociously mature phenotype. Indeed, cardiac gene expression measures in 11β-HSD2-/- fetuses were indicative of increased glucocorticoid exposure and maturation. This work reveals that impaired umbilical cord flow has a direct adverse effect on fetal cardiac function as a consequence of the fetal heart beating directly against the resistance of the placental bed. This also highlights 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.