Glucocorticoid levels rise dramatically in late gestation in mammals and are essential for organ maturation in preparation for birth. They are widely used clinically to mature the lungs of premature infants and hypomorphic GR mice die neonatally due to severe lung atelectasis. Here, we describe fetal lethality in GR null (GR−/−) mice with 51% loss at E17.5 (P<0.05) that could be due to impaired cardiac development. Histology showed reduced heart size in GR−/− fetuses from E16.5, co-incident with a peak in heart corticosterone content, which was undetectable at E14.5. Magnetic resonance imaging confirmed a 21.9±4.7% reduction in ventricular volume at E17.5 (P<0.05) yet no structural abnormalities were observed. In vivo high frequency ultrasound analysis revealed impaired left ventricular function in E17.5 GR−/− fetuses, with increased TEI-Doppler index (WT, 0.36±0.02 versus KO, 0.54±0.03, P<0.001), with heterozygous mice showing an intermediate phenotype (0.45±0.02; P<0.01 versus WT), and decreased E/A wave ratio (WT, 0.41±0.028 versus KO, 0.28±0.038). Impaired cardiac performance was accompanied by oedema in GR−/− fetuses (wet weight WT, 0.85±0.03 versus KO, 0.86±0.01, dry weight WT, 0.12±0.004 versus KO, 0.1±0.002, P<0.01; fetal Na/K ratio WT, 0.9±0.02 versus KO, 1.03±0.01, P<0.001), indicative of heart failure. The observed phenotype could not be attributed to deficiency in cardiac adrenaline content, which was normal at E17.5, nor were there any compensatory alterations in cardiac mineralocorticoid receptor mRNA levels. Cardiomyocytes of E17.5 GR−/− hearts displayed cellular defects, including underdeveloped myofibrils and dense nuclei. RNA analysis showed normal cardiac gene expression in GR−/− fetuses at E14.5 (prior to the glucocorticoid increase), but a lack of the normal maturational changes at E17.5 (e.g. increased α-myosin heavy chain, increased PGC1α, decreased UCP2). These data suggest that glucocorticoid action in late gestation heart is essential for its biochemical and functional maturation and lack of the normal maturational effects of glucocorticoids leads to congestive heart failure.
This work was supported by a British Heart Foundation studentship (to E R-Z) FS/08/065.