Abstract P1002: Impact Of Maternal Diabetes-associated Oxidative Stress On The Developing Endocardium

Abstract

Congenital heart defects (CHD) affect 1% of all live births and are the leading cause of birth defect-related mortality. The etiology of CHD is multifactorial as genomic variation and environmental factors act as contributors. Among the environmental teratogens, maternal pre-gestational diabetes mellitus and its concurrent maternal hyperglycemia (matHG) is associated with a ~5-fold increased risk of CHD. Oxidative stress (Ox-Stress) due to generation of excess reactive oxygen species is observed in embryonic hearts exposed to matHG in animal models, but its teratogenic effect on cardiac development is not understood. Additionally, we observed murine embryonic hearts exposed to matHG have reduced expression of Notch1, which is highly expressed in endocardial cells (EC) and reported a gene-environment interaction between matHG and Notch1 haploinsufficiency that results in CHD in mice. We hypothesize that matHG-induced Ox-Stress leads to the downregulation of endocardial Notch signaling and aberrant EC function leading to CHD. To investigate the effects of matHG-induced Ox-Stress on endocardial Notch signaling, we examined mouse embryos exposed to matHG with conditional deletion of Notch1 in EC. We used lineage tracing to detect differences in EC-derived structures in hyperglycemia and normoglycemia-exposed embryonic hearts. Finally, we asked whether modulating intracellular levels of Ox-Stress can rescue the CHD phenotypes observed with matHG exposure by generating mouse embryos with overexpression of the antioxidant gene, SOD1 . Results show conditional deletion of endocardial Notch1 in embryos exposed to matHG leads to highly penetrant CHD. We found increased Ox-Stress and reduced number of EC-derived mesenchymal cells in endocardial cushions of mouse hearts exposed to matHG. Finally, embryos with SOD1 overexpression have reduced Ox-Stress and decreased incidence of CHD compared to non-SOD1 overexpressing littermates. This works shows that matHG-induced Ox-Stress may be associated with aberrant EC and EC-derived cell function via disruption of Notch signaling. Mitigating Ox-Stress during cardiac development may lead to rescue of Notch signaling and EC function to reduce CHD incidence from matHG exposure.