Aberrant expression of hypoxia-inducible factor 1α in the fetal heart is associated with maternal undernutrition

Maternal undernutrition during pregnancy is a risk factor that impairs fetal growth and causes cardiovascular diseases. However, the underlying mechanism is still unknown. In this study, we evaluated the effect of maternal undernutrition on the expression levels of transcription factors in the fetal heart. Female mice were given low protein or regular food from 2 weeks before mating and during their pregnancy. The fetal hearts were collected on day 17.5 of gestation, about 1-2 days before birth. Maternal undernutrition resulted in a significant increase in the relative heart weight (heart weight/body weight) in female fetuses, but not in male fetuses. Microarray analysis revealed that expression levels of mRNAs for 133 transcription factors were changed in the fetal heart under maternal undernutrition. Among them, we focused on hypoxia-inducible factor 1 alpha (HIF1α) that is involved in the pathogenesis of cardiovascular diseases on adulthood. Quantitative real-time PCR analysis showed that the expression level of HIF1α mRNA was increased about 1.3-fold in male fetal heart under maternal undernutrition, but remained unchanged in female heart. Moreover, maternal undernutrition increased the mRNA level of prolyl hydroxylase 1 (PHD1), which contributes to degradation of HIF1α, in male heart but not in female heart. Immunohistochemical analysis showed the accumulation of HIF1α protein in the fetal heart of both sexes under maternal undernutrition, without the induction of HIF1α mRNA expression in female heart. These results suggest that maternal undernutrition may induce HIF1α expression in the fetal heart through the distinct mechanisms depending on the sex.