Estrogen normalizes maternal HFD-induced vascular dysfunction in offspring by regulating ATR

Previous studies have shown that female offspring are resistant to fetal high-fat diet (HFD)-induced programming of heightened vascular contraction; however, the underlying mechanisms remain unclear. The present study tested the hypothesis that estrogen plays a key role in protecting females from fetal programming of increased vascular contraction induced by maternal HFD exposure. Pregnant rats were fed a normal diet (ND) or HFD (60% kcal from fat). Ovariectomy (OVX) and 17β-estradiol (E₂) replacement were performed on 8-week-old female offspring. Aortas were isolated from adult female offspring. Maternal HFD exposure increased angiotensin II (Ang II)-induced contractions of the aorta in adult OVX offspring, which was abrogated by E₂ replacement. The AT₁ receptor (AT₁R) antagonist losartan (10 μM), but not the AT₂ receptor (AT₂R) antagonist PD123319 (10 μM), completely blocked Ang II-induced contractions in both ND and HFD offspring. In addition, HFD exposure caused a decrease in endothelium-dependent relaxations induced by acetylcholine (ACh) in adult OVX but not OVX-E₂ offspring. However, it had no effect on sodium nitroprusside (SNP)-induced endothelium-independent aorta relaxation in any of the six groups. Maternal HFD feeding increased AT₁R, but not AT₂R, leading to an increased AT₁R/AT₂R ratio in HFD-exposed OVX offspring, associated with selective decreases in DNA methylation at the AT_1aR promoter, which was ameliorated by E₂ replacement. Our results indicated that estrogen play a key role in sex differences of maternal HFD-induced vascular dysfunction and development of hypertensive phenotype in adulthood by differently regulating vascular AT₁R and AT₂R gene expression through a DNA methylation mechanism.