Cardiac corticosteroid receptors mediate the enlargement of the ovine fetal heart induced by chronic increases in maternal cortisol

Abstract

Previous studies have demonstrated that modest, physiologically relevant increases in maternal cortisol in late gestation result in enlargement of the fetal heart. In this study, we investigated the role of mineralocorticoid receptor (MR) or glucocorticoid receptor (GR) in this enlargement. Ewes with single fetuses were randomly assigned at w120 days of gestation to one of four groups: maternal cortisol infusion (1 mg/kg per day, cortisol); maternal cortisol infusion with fetal intrapericardial infusion of the MR antagonist (MRa) potassium canrenoate (600 mg/day; cortisolCMRa); maternal cortisol infusion with fetal intrapericardial infusion of the GR antagonist (GRa) mifepristone (50 mg/day, cortisolCGRa); and maternal saline infusion (control). At w130 days of gestation, fetal heart to body weight ratio and right ventricular (RV) and left ventricular (LV) free wall thicknesses were increased in the cortisol group when compared with control group. Fetal hearts from the cortisolCMRa group weighed significantly less, with thinner LV, RV, and interventricular septum walls, when compared with the cortisol group. Fetal hearts from the cortisolCGRa group had significantly thinner RV walls than the cortisol group. Fetal arterial pressure and heart rate were not different among groups at 130 days. Picrosirius red staining of fetal hearts indicated that the increased size was not accompanied by cardiac fibrosis. These results suggest that physiologic increases in maternal cortisol in late gestation induce fetal cardiac enlargement via MR and, to a lesser extent, by GR, and indicate that the enlargement is not secondary to an increase in fetal blood pressure or an increase in fibrosis within the fetal heart.

Elevated maternal cortisol leads to relative maternal hyperglycemia and increased stillbirth in ovine pregnancy

“…The finding that chronic elevation of maternal cortisol dramatically increased the incidence of fetal death and/or stillbirth was unexpected on the basis of our previous studies with shorter (10 -14 days) duration of cortisol infusion ending at 130 days gestation (13,28). Although the cause of fetal demise has yet to be established in these fetuses, there appears to be an association with impaired maternal glucose tolerance and with maternal hyperinsulinemia.…”

Embryo exposure to elevated cortisol level leads to cardiac performance dysfunction in zebrafish

“…BMPs are key morphogens regulating the expression of genes involved in organogenesis, including heart development Chen et al, 1997), providing a potential link between GR-mediated cortisol signaling and cardiac morphogenesis. There have been studies linking cortisol to abnormal heart development and cardiac gene expression in fetal sheep (Lumbers et al, 2004;Reini et al, 2008) and to cardiac hypertrophy in adult salmon (Johansen et al, 2011). However, few studies have examined the role of cortisol in the developmental regulation of cardiac function in fish.…”

Cortisol stimulates proliferation and apoptosis in the late gestation fetal heart: differential effects of mineralocorticoid and glucocorticoid receptors

“…We have used an ovine model of chronic maternal stress using exogenous cortisol infusion to increase maternal cortisol concentrations to those comparable to that seen acutely after transport in ewes (31,57). We have found that chronic elevation of maternal cortisol concentrations caused a slowing of overall fetal growth but an increase in fetal heart weight, ventricular wall thickness, and heart weight-tobody weight ratio (28,46). These increases in maternal cortisol produce a modest increase in fetal cortisol relative to the concentrations that are achieved near term, without an increase in fetal blood pressure or an increase in cardiac fibrosis (46).…”