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

Area of Science:

• Cardiovascular Physiology
• Endocrinology
• Developmental Programming

Background:

• Maternal high-fat diet (HFD) can program offspring for cardiovascular issues.
• Female offspring typically show resistance to HFD-induced vascular dysfunction.
• Mechanisms underlying this sex-based protection remain largely unknown.

Purpose of the Study:

• To test if estrogen protects female offspring from HFD-induced vascular programming.
• To investigate estrogen's role in regulating vascular angiotensin II receptor (AT1R/AT2R) expression and DNA methylation.

Main Methods:

• Pregnant rats fed normal diet (ND) or HFD.
• Female offspring underwent ovariectomy (OVX) or 17β-estradiol (E2) replacement.
• Vascular function (contractions/relaxations) and AT1R/AT2R expression/methylation analyzed in adult aortas.

Main Results:

• Maternal HFD increased aortic contractions in OVX offspring, reversed by E2.
• HFD decreased endothelium-dependent relaxation in OVX offspring, but not in E2-replaced offspring.
• HFD increased AT1R/AT2R ratio via decreased AT1aR promoter methylation, reversed by E2.

Conclusions:

• Estrogen is crucial in sex differences in fetal HFD programming of vascular function.
• Estrogen protects against HFD-induced vascular dysfunction by regulating AT1R/AT2R gene expression via DNA methylation.
• This mechanism contributes to preventing adult hypertensive phenotypes.