Perinatal hypoxia-mediated neurodevelopment abnormalities in congenital heart disease mouse model.

BACKGROUND: Cyanotic congenital heart disease (CHD) in children has been associated with neurodevelopmental abnormalities, although the underlying mechanisms remain largely unknown. Multiple factors are likely involved in this process. This research aims to explore the potential effects of hypoxia and vascular system-derived factors in neurodevelopmental outcomes in offspring. METHODS: Mouse aorta endothelial cells (MEC) and amygdala neurons were isolated to investigate the effects of hypoxia on pro-inflammatory cytokine release, gene expression, redox balance, mitochondrial function, and epigenetic modifications. A CHD mouse model was established to evaluate the impact of perinatal hypoxia on fetal brain development. Estrogen receptor β (ERβ) expression in endothelial cells was modulated using Tie2-driven lentivirus both in vitro and in vivo study to assess the vascular system's contribution to hypoxia-mediated neurodevelopmental abnormalities. RESULTS: Hypoxia exposure, along with factors released from MEC, led to altered gene expression, oxidative stress, mitochondrial dysfunction, and epigenetic modifications in amygdala neurons. In the CHD mouse model, perinatal hypoxia resulted in compromised vascular function, altered gene expression, disrupted redox balance in brain tissues, and impaired behavioral outcomes in offspring. Prenatal expression of ERβ in endothelial cells partially ameliorated these neurodevelopmental abnormalities, while prenatal knockdown of ERβ mimicked the effects of perinatal hypoxia. CONCLUSIONS: Hypoxia, combined with endothelial cell-derived factors, induces epigenetic changes in neurons. In the CHD mouse model, perinatal hypoxia causes vascular dysfunction, altered gene expression, and redox imbalance in brain tissues, leading to behavioral impairments in offspring. Prenatal expression of ERβ in endothelial cells mitigates these effects, suggesting that modulating gene expression in the vascular system during pregnancy could play a protective role against hypoxia-induced neurodevelopmental abnormalities in CHD.