The effect of prenatal hypoxia on cardiomyocyte development and postnatal heart health.

Abstract

Environmental factors can act in early life to increase the risk of disease in adulthood. Animal models demonstrate that intrauterine growth restriction (IUGR) results in a greater susceptibility to cardiac ischaemia/reperfusion injury and reduced cardiac power during reperfusion than Control offspring in postnatal life. Despite having an equivalent utilisation of fatty acids and glucose for cardiac ATP production prior to ischaemia/reperfusion, IUGR offspring have decreased utilisation of fatty acids and increased reliance on glycolysis for ATP production compared to Control offspring during reperfusion. We therefore aimed to determine if IUGR reduces cardiomyocyte endowment and alters the expression of cardiometabolic genes in postnatal life. We determined that IUGR due to placental restriction from conception, which causes chronic fetal hypoxaemia and hypoglycaemia, reduced the number of cardiomyocytes in the heart of sheep in late gestation. In addition, IUGR fetuses had the same percentage of apoptotic cardiomyocytes, length of coronary capillaries and expression of the majority of genes whose upregulation occurs during hypoxia, compared to Controls. Furthermore, we found that IUGR reduced cardiomyocyte endowment in adolescent guinea pigs if they were exposed to Maternal Hypoxia (MH) and were female, but not if they were male or if IUGR was induced by Maternal Nutrient Restriction (MNR). IUGR offspring exposed to MH had increased expression of the transcriptional regulator of fatty acid metabolism, PPARα, and increased expression of fatty acid transporters, FATP1, FAPT6 and FABPpm, but offspring exposed to MNR only had an increased expression of FATP6, compared to Control. Interestingly, IUGR male offspring, but not female offspring, had decreased expression of factors in the sarcoplasm that regulate fatty acid activation (FACS) and transport of active fatty acids into the mitochondria for fatty acid β-oxidation (AMPKα₂ and ACC) if exposed to MNR, but a decrease in only FACS and AMPKα₂ if exposed to MH. Interestingly, only IUGR females exposed to MH had increased activity of the metabolic fuel gauge, AMPK, suggesting that a decrease in ATP may be related to the deficit in cardiomyocyte endowment. In conclusion, we have shown that in response to placental restriction, reducing cardiomyocyte endowment whilst maintaining the total length of coronary capillaries, results in the heart being normoxic, despite chronic hypoxaemia, in late gestation. Furthermore, this data suggests that females are more likely to have reduced cardiomyocyte endowment, following IUGR, in adolescence than males and that cardiomyocytes may be influenced by hypoxia more than nutrient restriction. Furthermore, we have demonstrated that IUGR programs changes in cardiometabolic gene expression in the absence of other IUGR pathologies such as cardiac hypertrophy, hypertension and increased plasma fatty acid and cortisol concentrations.