Synergistic Effects of Maternal Diabetes and HIF-1α Dysregulation on Embryonic Development of Cardiac Sympathetic Innervation

Abstract

Introduction: Maternal diabetes during embryonic development has been associated with adverse health outcomes, including an increased risk of obesity, metabolic dysfunction, and cardiovascular diseases. Cardiac sympathetic innervation plays a critical role in regulating heart function, and any alternation in its development or function may lead to a range of health issues, from sudden infant death syndrome to common adult diseases such as hypertension or heart failure.

Methods: In this study, we used a transgenic mouse model with a conditional deletion of Hif1a (Hif1aCKO) in sympathetic neurons, in combination with our established model of maternal diabetes induced by streptozocin.

Results: Our preliminary data showed that total sympathetic chain size was significantly smaller in diabetic Hif1aCKO embryos compared to the controls. Hif1aCKO hearts developing under the influence of maternal diabetes showed impaired sympathetic innervation. Diabetic environment effected the branching and thickness of innervation, together with the density of sympathetic neurons. Furthermore, the size of the adrenal gland and the number of chromaffin cells in the adrenal medulla was decreased in diabetic Hif1aCKO embryos. RNA sequencing revealed changes between the transcriptome of sympathetic neurons from mutant and control embryos.

Conclusions: Our study indicate that maternal diabetes and Hif1a deficiency have combinatorial effects on the development of the cardiac sympathetic nervous system. Consequently, HIF1α dysregulation may contribute to various sympathetic abnormalities underlying cardiac pathologies, including heart failure and sudden cardiac death. These findings highlight the importance of considering maternal health and genetic factors in the development of adverse cardiac outcomes in offspring.