Role of eNOS in fetal heart development during pregestational diabetes with maternal exercise.
Abstract
Pregestational diabetes (PGD) significantly increases the risk of congenital heart defect (CHD) development by more than five-fold. Maternal exercise enhances endothelial nitric oxide synthase (eNOS) activity, benefiting embryos, though the causal relationship remains unclear. This study investigated the role of eNOS in mediating the protective effects of maternal exercise on fetal heart development in an eNOS+/- type 1 diabetic mouse model of PGD. Diabetes was induced by streptozotocin (STZ) in adult eNOS+/- and eNOS+/+ females. eNOS+/- females were bred with wild-type (eNOS+/+) males and eNOS+/+ females were bred with eNOS+/- males, to produce eNOS+/+ and eNOS+/- offspring in the same litter. Diabetic dams were placed in a cage with or without a running wheel as a voluntary exercise model. Fetuses were collected from eNOS+/+ and eNOS+/- dams on embryonic day 18.5 to assess heart morphology. E12.5 hearts were analyzed for cell proliferation, apoptosis, oxidative stress, and eNOS protein levels. Despite maternal exercise enhancing coronary artery density and normalizing cellular proliferation in embryonic hearts, it did not reduce the incidence of CHDs or PGD-induced oxidative stress, regardless of fetal genotype. PGD induced CHDs including cardiac septation, outflow tract and valve defects. Our findings show that maternal exercise does not improve fetal heart outcomes in eNOS+/- mice during PGD.