Abstract
Endogenous glucocorticoid action is important in the structural and functional maturation of the fetal heart. In fetal mice, although glucocorticoid concentrations are extremely low before E14.5, glucocorticoid receptor (GR) is expressed in the heart from E10.5. To investigate whether activation of cardiac GR prior to E14.5 induces precocious fetal heart maturation, we administered dexamethasone in the drinking water of pregnant dams from E12.5 to E15.5. To test the direct effects of glucocorticoids upon the cardiovascular system we used SMGRKO mice, with Sm22-Cre-mediated disruption of GR in cardiomyocytes and vascular smooth muscle. Contrary to expectations, echocardiography showed no advancement of functional maturation of the fetal heart. Moreover, litter size was decreased 2 days following cessation of antenatal glucocorticoid exposure, irrespective of fetal genotype. The myocardial performance index and E/A wave ratio, markers of fetal heart maturation, were not significantly affected by dexamethasone treatment in either genotype. Dexamethasone treatment transiently decreased the myocardial deceleration index (MDI; a marker of diastolic function), in control fetuses at E15.5, with recovery by E17.5, 2 days after cessation of treatment. MDI was lower in SMGRKO than in control fetuses and was unaffected by dexamethasone. The transient decrease in MDI was associated with repression of cardiac GR in control fetuses following dexamethasone treatment. Measurement of glucocorticoid levels in fetal tissue and hypothalamic corticotropin-releasing hormone (Crh) mRNA levels suggest complex and differential effects of dexamethasone treatment upon the hypothalamic–pituitary–adrenal axis between genotypes. These data suggest potentially detrimental and direct effects of antenatal glucocorticoid treatment upon fetal heart function.
Highlights
Levels of glucocorticoid hormones rise markedly shortly prior to birth to promote fetal organ and tissue maturation in preparation for birth and subsequent postnatal life (Fowden et al 1998)
We demonstrated an important role for endogenous glucocorticoids, acting via the glucocorticoid receptor (GR), in fetal heart maturation
Whilst the expected corticotropin-releasing hormone (Crh) downregulation was seen in dexamethasone-treated SMGRKO fetuses at E15.5, there was no significant effect in control fetuses at this age, nor were there any significant treatment differences between fetuses at E17.5 (Supplementary Fig. 6)
Summary
Levels of glucocorticoid hormones rise markedly shortly prior to birth to promote fetal organ and tissue maturation in preparation for birth and subsequent postnatal life (Fowden et al 1998). Studies in fetal sheep hearts have shown that late gestation maternal hypercortisolaemia impacts the myocyte transcriptome, with some changes indicative of precocious maturation, but others not (Richards et al 2014). Whether these effects are mediated by alterations in maternal or placental physiology or reflect direct actions upon fetal cardiomyocytes is unknown. A clear consensus regarding the direct impact of exogenous glucocorticoid upon the fetal heart is yet to emerge
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