Cardiovascular malformations are the most common manifestation of diabetic embryopathy. The molecular mechanisms underlying the teratogenic effect of maternal diabetes have not been fully elucidated. Using genome-wide expression profiling, we previously demonstrated that exposure to maternal diabetes resulted in dysregulation of the hypoxia-inducible factor 1 (HIF-1) pathway in the developing embryo. We thus considered a possible link between HIF-1-regulated pathways and the development of congenital malformations. HIF-1α heterozygous-null (Hif1a(+/-)) and wild type (Wt) littermate embryos were exposed to the intrauterine environment of a diabetic mother to analyze the frequency and morphology of congenital defects, and assess gene expression changes in Wt and Hif1a(+/-) embryos. We observed a decreased number of embryos per litter and an increased incidence of heart malformations, including atrioventricular septal defects and reduced myocardial mass, in diabetes-exposed Hif1a(+/-) embryos as compared to Wt embryos. We also detected significant differences in the expression of key cardiac transcription factors, including Nkx2.5, Tbx5, and Mef2C, in diabetes-exposed Hif1a(+/-) embryonic hearts compared to Wt littermates. Thus, partial global HIF-1α deficiency alters gene expression in the developing heart and increases susceptibility to congenital defects in a mouse model of diabetic pregnancy.

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