A Transcriptomic Model of Postnatal Cardiac Effects of Prenatal Maternal Cortisol Excess in Sheep

Abstract

In utero treatment with glucocorticoids have been suggested to reprogram postnatal cardiovascular function and stress responsiveness. However, little is known about the effects of prenatal exposure to the natural corticosteroid, cortisol, on postnatal cardiovascular system or metabolism. We have demonstrated an increased incidence of stillbirth in sheep pregnancies in which there is mild maternal hypercortisolemia caused by infusion of 1 mg/kg/d cortisol. In order to model corticosteroid effects in the neonate, we created a second model in which cortisol was infused for 12 h per day for a daily infusion of 0.5 mg/kg/d. In this model we had previously found that neonatal plasma glucose was increased and plasma insulin was decreased compared to those in the control group, and that neonatal ponderal index and kidney weight were reduced and left ventricular wall thickness was increased in the 2 week old lamb. In this study, we have used transcriptomic modeling to better understand the programming effect of this maternal hypercortisolemia in these hearts. This is a time when both terminal differentiation and a shift in the metabolism of the heart from carbohydrates to lipid oxidation are thought to be complete. The transcriptomic model indicates suppression of genes in pathways for fatty acid and ketone production and upregulation of genes in pathways for angiogenesis in the epicardial adipose fat (EAT). The transcriptomic model indicates that RNA related pathways are overrepresented by downregulated genes, but ubiquitin-mediated proteolysis and protein targeting to the mitochondria are overrepresented by upregulated genes in the intraventricular septum (IVS) and left ventricle (LV). In IVS the AMPK pathway and adipocytokine signaling pathways were also modeled based on overrepresentation by downregulated genes. Peroxisomal activity is modeled as increased in EAT, but decreased in LV and IVS. Our results suggest that pathways for lipids as well as cell proliferation and cardiac remodeling have altered activity postnatally after the in utero cortisol exposure. Together, this model is consistent with the observed increase in cardiac wall thickness at necropsy and altered glucose metabolism observed in vivo , and predicts that in utero exposure to excess maternal cortisol will cause postnatal cardiac hypertrophy and altered responses to oxidative stress.

Inclusion of wheat aleurone in gestation diets improves postprandial satiety, stress status and stillbirth rate of sows

“…The stillbirth rate was reported to increase with higher levels of cortisol in pregnant sheep ( Antolic et al., 2019 ). In our study, the WA group had lower saliva concentrations of pre-prandial cortisol than the control diet group, which contributed to the reduction or downward trend for the stillbirth rate in the 15% and 30% WA groups, respectively.…”

Application of Carbon-13 Isotopomer Analysis to Assess Perinatal Myocardial Glucose Metabolism in Sheep

“…This time was chosen in order to reliably get fetal data prior to the onset of labor. Transcriptomic data [21] from hearts at this age of gestation suggest changes in cardiac metabolism in the model studied in our lab (chronic maternal stress/hypercortisolemia), and so this age was our starting point for establishing the stable isotope tracer method for use in subsequent studies. Additionally, since the ewes used in the study were not in labor yet, the observed metabolic fluxes are not labor contraction stimulated changes.…”

Environmental Alterations during Embryonic Development: Studying the Impact of Stressors on Pluripotent Stem Cell-Derived Cardiomyocytes

“…Indeed, a high concentration of maternal cortisol throughout late gestation alters the regular cardiac gene expression pattern in the ovine foetus [230,231], which persists into postnatal development. Transcriptomic profile of lipid metabolism, cell proliferation and cardiac remodelling, are affected postnatally after the in utero cortisol exposure, together with increased cardiac wall thickness and altered glucose metabolism [232]. These alterations may cause postnatal cardiac hypertrophy and altered responses to oxidative stress [232].…”

“…Transcriptomic profile of lipid metabolism, cell proliferation and cardiac remodelling, are affected postnatally after the in utero cortisol exposure, together with increased cardiac wall thickness and altered glucose metabolism [232]. These alterations may cause postnatal cardiac hypertrophy and altered responses to oxidative stress [232]. In addition to higher cortisol release, stress triggers the increase of norepinephrine and inflammation, which affect the foetal environment and lead to infant health complications.…”