Maternal high-fat diet increases vascular contractility in adult offspring in a sex-dependent manner.

A maternal high-fat diet (HFD) is a risk factor for cardiovascular diseases in offspring. The aim of the study was to determine whether maternal HFD causes the epigenetic programming of vascular angiotensin II receptors (ATRs) and leads to heightened vascular contraction in adult male offspring in a sex-dependent manner. Pregnant rats were treated with HFD (60% kcal fat). Aortas were isolated from adult male and female offspring. Maternal HFD increased phenylephrine (PE)-and angiotensin II (Ang II)-induced contractions of the aorta in male but not female offspring. NG-nitro-L-arginine (ʟ-NNA; 100 μM) abrogated the maternal HFD-induced increase in PE-mediated contraction. HFD caused a decrease in endothelium-dependent relaxations induced by acetylcholine in male but not female offspring. However, it had no effect on sodium nitroprusside-induced endothelium-independent relaxations of aortas regardless of sex. The AT1 receptor (AT1R) antagonist losartan (10 μM), but not the AT2 receptor (AT2R) antagonist PD123319 (10 μM), blocked Ang II-induced contractions in both control and HFD offspring in both sexes. Maternal HFD increased AT1R but decreased AT2R, leading to an increased ratio of AT1R/AT2R in HFD male offspring, which was associated with selective decreases in DNA methylation at the AT1aR promoter and increases in DNA methylation at the AT2R promoter. The vascular ratio of AT1R/AT2R was not significantly different in HFD female offspring compared with the control group. Our results indicated that maternal HFD caused a differential regulation of vascular AT1R and AT2R gene expression through a DNA methylation mechanism, which may be involved in HFD-induced vascular dysfunction and the development of a hypertensive phenotype in adulthood in a sex-dependent manner.