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

Hypertension Research volume 45, pages 1743–1753 (2022)Cite this article

Abstract

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 AT1aR 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.

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Acknowledgements

We would like to thank Guiping Zhang for the technical guidance.

Funding

This study was supported by the Natural Science Foundation of Guangdong Province (2018A030313719) and the High-level University Construction Fund of Guangdong Province (06-410-2107243).

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  1. These authors contributed equally: Fangyuan Chen, Runzhu Zhao.

Authors and Affiliations

  1. Department of Pharmacology, Guangzhou Municipal and Guangdong Provincial Key Laboratory of Molecular Target & Clinical Pharmacology, the NMPA and State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences and the Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, 511436, China

    Fangyuan Chen, Runzhu Zhao, Haichuan Zhang, Cailing Huang, Yinghua Liu & Qin Xue

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Chen, F., Zhao, R., Zhang, H. et al. Estrogen normalizes maternal HFD-induced vascular dysfunction in offspring by regulating ATR. Hypertens Res 45, 1743–1753 (2022). https://doi.org/10.1038/s41440-022-01002-2

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