The effects of endogenous and exogenous glucocorticoids on placental vascular development and hemodynamic function

The effects of endogenous and exogenous glucocorticoids on placental vascular development and hemodynamic function

 

Appropriate development and function of the placental vascular network is critical for maintaining fetal growth. In pregnant rats, early to mid-gestation exposure to dexamethasone, a potent synthetic glucocorticoid, reduces the complexity of placental vasculature, contributing to adverse fetal outcomes. Dexamethasone (or the related betamethasone) is often administered to pregnant women at risk of preterm delivery, to reduce neonatal mortality should preterm delivery ensue. However, this precedes the natural rise in endogenous glucocorticoids that normally occurs shortly prior to parturition. Two questions are addressed: first, how the late gestation increase in glucocorticoids affect placental hemodynamic parameters and second, how placental hemodynamic parameters are impacted following exogenous glucocorticoid exposure, potentially resulting in abnormal fetal development.

Research Methods and Objectives

Heterozygous glucocorticoid receptor (GR) knockout mice are being used to investigate the role of endogenous glucocorticoids in placental vascularisation and hemodynamics. Heterozygous matings produce offspring with normal, haploinsufficient or absent GR-mediated glucocorticoid action. To simulate clinical administration of exogenous glucocorticoids, pregnant C57BL/6 mice receive an IP injection of vehicle or dexamethasone (500μg/kg) at gestational day [E] 13.5 or E16.5, with analysis of placental and fetal parameters 24h later. In both experiments, in vivo pre-clinical ultrasound scanning is conducted in separate cohorts, at E14.5 or E17.5, to measure umbilical arterial blood flow (a key regulator of fetal and placental growth) and fetal heart function. Future experiments will analyse placental morphology and molecular pathways to develop a comprehensive understanding of how these parameters translate to hemodynamic function of glucocorticoid-exposed placentas.

 

Principal investigators: Dr Caitlin Wyrwoll^ , Prof Karen Chapman

Co-Investigators: Emma Panting^, Adrian Thomson, Dr Carmel Moran, Dr Peter Mark^, Prof Brendan Waddell^

^School of Human Sciences, The University of Western Australia