Elevated cortisol concentration in preterm sheep fetuses impacts heart development

The prepartum rise in cortisol promotes cardiac development and maturation. Here, we investigated the impact of elevated circulating cortisol during mid-late gestation on cardiac growth and metabolism in fetal sheep. Saline or cortisol (2-3 mg in 4.4 mL/24 h) was infused into the fetal jugular vein from 109 to 116 days gestation (dG, term = 150 dG), and fetal heart tissue was collected at 116 dG. Glucocorticoid concentrations, gene and protein expression were measured in fetal left ventricle (LV) tissue. Intrafetal cortisol infusion increased cardiac cortisol concentration but downregulated the protein abundance of glucocorticoid receptor (GR) isoforms (GRα-A, GR-P, GR-A, GRα-D2 and GRα-D3). The gene and protein expression of markers of cardiac hyperplastic growth (IGF1, IGF-1R, TGFβ and AGT) were downregulated, while a protein marker of DNA replication (proliferating cell nuclear antigen) was upregulated by cortisol infusion. Cardiac protein and/or gene expression of complex I of the electron transport chain, SOD2, GLUT-4 (gene and protein), and phosphorylated IRS-1, were upregulated in response to elevated fetal cortisol concentration. Intrafetal cortisol infusion downregulated gene expression of PDK4, which mediates the metabolic switch from glucose to fatty acid metabolism. Cardiac expression of molecular markers involved in cardiovascular protection (SIRT-1, HO1, LAMP1 and SK1) were also downregulated in the cortisol group. In conclusion, these findings suggest that chronic cortisol exposure in preterm fetuses alters heart development, promoting cardiac maturation and potentially increasing the risk of cardiovascular disease later in life if these changes persist into adulthood.