Preservation of Vascular Endothelial Function in Late-Onset Postmenopausal Women

Postmenopausal women (PMW) who complete menopause at a late age (55+ years) have lower cardiovascular disease risk than PMW who complete menopause at a normal age (45-54 years). However, the influence of late-onset menopause on vascular endothelial dysfunction is unknown. Moreover, the mechanisms by which a later age at menopause may modulate endothelial function remain to be determined.

We measured endothelial function (brachial artery flow-mediated dilation [FMD_BA]) in age-matched late- and normal-onset PMW and a young premenopausal reference group. We determined mitochondrial reactive oxygen species (mitoROS)-related suppression of endothelial function (change in FMD_BA with an acute dose of the mitochondria-targeted antioxidant MitoQ; ΔFMD_{BA, MTQ}) in PMW. The effects of serum from late- and normal-onset PMW and premenopausal women on mitoROS bioactivity in human aortic endothelial cells in culture were assessed. Metabolomics analyses in combination with serum metabolite level normalization and human aortic endothelial cell serum exposure experiments were performed to identify the circulating factors contributing to the serum effects on endothelial cell mitoROS bioactivity.

FMD_BA in PMW was lower than in premenopausal women. However, FMD_BA was >50% higher in late- versus normal-onset PMW and positively related to age at menopause. ΔFMD_{BA, MTQ} was >50% lower in late- versus normal-onset PMW. Serum from normal-onset PMW but not late-onset PMW induced higher mitoROS bioactivity in human aortic endothelial cells compared with serum from premenopausal women. MitoROS bioactivity was negatively related to FMD_BA and age at menopause. Seventeen metabolites significantly differed between late- and normal-onset PMW; 15 were lipid specific; 8 were triglyceride derived. TG(16:0) was most strongly correlated with mitoROS bioactivity. Normalization of TG(16:0) concentrations in serum from premenopausal women and late-onset PMW to match serum levels in normal-onset PMW abrogated differences in mitoROS bioactivity in serum-treated human aortic endothelial cells.

Late-onset menopause is associated with preservation of endothelial function, which is mediated by lower mitoROS-associated oxidative stress. A more favorable profile of circulating lipid metabolites, specifically triglyceride-derived metabolites, contributes to lower endothelial cell mitoROS in late-onset PMW. These findings provide new insight into the possible mechanisms of reduced cardiovascular disease risk in late-onset menopause.