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Thesis Format

Integrated Article

Degree

Master of Science

Program

Physiology and Pharmacology

Collaborative Specialization

Developmental Biology

Supervisor

Feng, Qingping

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.

Summary for Lay Audience

As babies develop, they are influenced by their mother’s health and health issues can impair proper development, specifically in their heart. Pregestational diabetes (PGD) is an example of such a health issue as it increases the risk of heart defects developing in babies. Pregestational means the mother has diabetes before she becomes pregnant and therefore it can be Type 1 or Type 2 diabetes. PGD causes the baby to produce harmful molecules called reactive oxygen species which cause cells in the heart to develop abnormally. Previous studies suggest that maternal exercise may help protect against the heart defects caused by PGD, potentially by boosting a molecule called endothelial nitric oxide synthase (eNOS) which reduces the production of the harmful reactive oxygen species. However, it’s still unclear if eNOS is the key factor in this protective effect.

To explore this, we used a mouse model where diabetes was induced in female mice with varying levels of eNOS, and the mice were allowed to either exercise voluntarily or remain sedentary. Near the end of pregnancy, we collected fetal mouse hearts to see if exercise reduced heart defects. We also collected hearts at an earlier time point in pregnancy to assess reasons for the changes to development responsible for causing heart defects.

Maternal exercise did not reduce the effects of the mom’s PGD on the babies as the number of defects was similar to babies only exposed to PGD. We believe this is because the amount of harmful reactive oxygen species produced in babies from mom’s with PGD and mom’s with PGD and exercise were very similar. Exercise did improve certain aspects of heart development. For example, it increased the number of blood vessels in the heart muscle, and it increased the overall survival and the number of babies the diabetic mice had. In summary, while maternal exercise helps some aspects of development in diabetic pregnancies with lower eNOS levels, it doesn’t appear to lower the risk of heart defects.

Creative Commons License

Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License.

Available for download on Friday, December 04, 2026

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