Maternal undernutrition during pregnancy alters the epigenetic landscape and the expression of endothelial function genes in male progeny

Abstract

Recent studies point to the important role of in utero malnutrition in gene programming and in the development of vascular diseases. We hypothesize that maternal undernutrition affects vascular function in the offspring by promoting epigenetic changes that drive the differential expression of genes involved in endothelial function. To test this, we exposed mice to nutrient deprivation in utero and analyzed its effect on global DNA methylation and expression of endothelium-specific genes in the pulmonary endothelium of the adult progeny. Mice were kept either on ad libitum (AL) or energy-restricted (ER) diet during the second and third trimesters of gestation. Mice in the ER group received 65% of energy compared to mice in the AL diet group. Pulmonary endothelial cells were isolated from 6-week-old male offspring mice (AL-F1 and ER-F1). The expression of genes in the pulmonary endothelium was analyzed using quantitative reverse-transcription polymerase chain reaction array and confirmed by qRT-PCR. Several genes including fibronectin 1 and plasminogen activator inhibitor 1 were upregulated in the endothelium of male ER-F1 mice, whereas the expression of genes involved in regulation of histone acetylation was significantly attenuated. At the same time, the global DNA methylation did not change in pulmonary endothelial cells of ER-F1 mice compared to AL-F1 mice. Overall, we found that maternal undernutrition during pregnancy affects the expression of genes involved in regulation of endothelial cell function in the pulmonary vasculature of male progeny, which could potentially promote pulmonary vascular remodeling.