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 (E 2 ) 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 E 2 replacement. The AT 1 receptor (AT 1 R) antagonist losartan (10 μM), but not the AT 2 receptor (AT 2 R) 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-E 2 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 AT 1 R, but not AT 2 R, leading to an increased AT 1 R/AT 2 R ratio in HFD-exposed OVX offspring, associated with selective decreases in DNA methylation at the AT 1a R promoter, which was ameliorated by E 2 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 AT 1 R and AT 2 R gene expression through a DNA methylation mechanism.