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 17 beta-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 mu M), but not the AT(2) receptor (AT(2)R) antagonist PD123319 (10 mu M), 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.

Automated summary

This study found that female offspring are resistant to enhanced vascular contraction caused by maternal high-fat diet (HFD). Estrogen plays a key role in protecting females from this programming by regulating the DNA methylation mechanism that controls vascular receptor gene expression.