Significance The sympathetic nervous system plays a critical role in stimulating heart rate and contractility to increase cardiac output and thereby insure adequate tissue O 2 delivery. Altered sympathetic output contributes to cardiac pathologies, such as sudden cardiac death and heart failure. Our data provide insight into the role of the transcription factor hypoxia-inducible factor 1α (HIF-1α) in the development of sympathetic ganglion neurons and cardiac sympathetic innervation. We found that genetic deletion of HIF-1α resulted in increased cell death and decreased proliferation of neuronal progenitors of the sympathetic system. These findings suggest that dysregulated HIF-1α expression may contribute to cardiac dysfunction and disease associated with defects in the cardiac sympathetic system by affecting the function and survival of sympathetic neurons.

The heart is able to metabolize any substrate, depending on its availability, to satisfy its energy requirements. Under normal physiological conditions, about 95% of ATP is produced by oxidative phosphorylation and the rest by glycolysis. Cardiac metabolism undergoes reprograming in response to a variety of physiological and pathophysiological conditions. Hypoxia-inducible factor 1 (HIF-1) mediates the metabolic adaptation to hypoxia and ischemia, including the transition from oxidative to glycolytic metabolism. During embryonic development, HIF-1 protects the embryo from intrauterine hypoxia, its deletion as well as its forced expression are embryonically lethal. A decrease in HIF-1 activity is crucial during perinatal remodeling when the heart switches from anaerobic to aerobic metabolism. In the adult heart, HIF-1 protects against hypoxia, although its deletion in cardiomyocytes affects heart function even under normoxic conditions. Diabetes impairs HIF-1 activation and thus, compromises HIF-1 mediated responses under oxygen-limited conditions. Compromised HIF-1 signaling may contribute to the teratogenicity of maternal diabetes and diabetic cardiomyopathy in adults. In this review, we discuss the function of HIF-1 in the heart throughout development into adulthood, as well as the deregulation of HIF-1 signaling in diabetes and its effects on the embryonic and adult heart.

Epidemiological studies show that maternal diabetes predisposes offspring to cardiovascular and metabolic disorders. However, the precise mechanisms for the underlying penetrance and disease predisposition remain poorly understood. We examined whether hypoxia-inducible factor 1 alpha, in combination with exposure to a diabetic intrauterine environment, influences the function and molecular structure of the adult offspring heart.

Hypoxia inducible factor 1 (HIF-1) activates protective pathways to counteract hypoxia and prevent tissue damage in conjunction with renal injury. The aim of this study was to evaluate a role of HIF-1 in diabetes-induced kidney damage.

Cardiovascular defects are one of the most common congenital defects associated with maternal diabetes. Based on whole embryo gene expression microarray analysis, 11 genes were chosen for temporal expression analysis of diabetes-exposed hearts. The majority of the selected genes were deregulated in diabetes-exposed hearts compared to our controls at E13.5, E14.5, and E18.5. We showed increased hypoxia and HIF-1α protein levels in diabetes-exposed hearts at E10.5, which is a critical time point for the induction of developmental defects associated with diabetic embryopathy. Additionally, we found increased cardiac Vegfa levels that might trigger developmental abnormalities associated with diabetic embryopathy. Our results show that maternal diabetes affects the temporal expression pattern of gene encoding molecules involved in heart development and tissue remodelling and that these molecules might affect heart maturation processes and thus, the final outcome of diabetic pregnancies.