Oral Presentation The Annual Scientific Meeting of the Endocrine Society of Australia and the Society for Reproductive Biology 2014

Manipulating placental vasculature to improve fetal health outcomes (#55)

Caitlin Wyrwoll 1
  1. The University of Western Australia, Nedlands, WA, Australia
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.