Darvish Sanna, Murray Kevin O, Ludwig Katelyn R, Avalani Krisha H, Craighead Daniel H, Freeberg Kaitlin A, Bevers Shaun, Reisz Julie A, D'Alessandro Angelo, Moreau Kerrie L, Seals Douglas R, Rossman Matthew J
Department of Integrative Physiology, University of Colorado Boulder (S.D., K.O.M., K.R.L., K.H.A., D.H.C., K.A.F., D.R.S., M.J.R.).
School of Kinesiology, University of Minnesota, Minneapolis (D.H.C.).
Circ Res. 2025 Feb 28;136(5):455-469. doi: 10.1161/CIRCRESAHA.124.325639. Epub 2025 Jan 31.
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]) 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 with an acute dose of the mitochondria-targeted antioxidant MitoQ; ΔFMD) 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 in PMW was lower than in premenopausal women. However, FMD was >50% higher in late- versus normal-onset PMW and positively related to age at menopause. ΔFMD 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 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.
绝经较晚（55岁及以上）的绝经后女性（PMW）患心血管疾病的风险低于正常绝经年龄（45 - 54岁）的PMW。然而，晚发性绝经对血管内皮功能障碍的影响尚不清楚。此外，绝经年龄较大可能调节内皮功能的机制仍有待确定。
我们测量了年龄匹配的晚发性和正常绝经年龄的PMW以及年轻的绝经前参照组的内皮功能（肱动脉血流介导的血管舒张 [FMD]）。我们测定了PMW中线粒体活性氧（mitoROS）相关的内皮功能抑制（使用急性剂量的线粒体靶向抗氧化剂MitoQ后FMD的变化；ΔFMD）。评估了晚发性和正常绝经年龄的PMW以及绝经前女性的血清对培养的人主动脉内皮细胞中mitoROS生物活性的影响。进行了代谢组学分析，并结合血清代谢物水平归一化和人主动脉内皮细胞血清暴露实验，以确定导致血清对内皮细胞mitoROS生物活性产生影响的循环因子。
PMW的FMD低于绝经前女性。然而，晚发性PMW的FMD比正常绝经年龄的PMW高50%以上，且与绝经年龄呈正相关。晚发性PMW的ΔFMD比正常绝经年龄的PMW低50%以上。与绝经前女性的血清相比，正常绝经年龄的PMW而非晚发性PMW的血清在人主动脉内皮细胞中诱导了更高的mitoROS生物活性。MitoROS生物活性与FMD和绝经年龄呈负相关。晚发性和正常绝经年龄的PMW之间有17种代谢物存在显著差异；15种是特定脂质；8种源自甘油三酯。TG(16:0)与mitoROS生物活性的相关性最强。将绝经前女性和晚发性PMW血清中的TG(16:0)浓度归一化以匹配正常绝经年龄的PMW的血清水平，消除了血清处理的人主动脉内皮细胞中mitoROS生物活性的差异。
晚发性绝经与内皮功能的保留有关，这是由较低的mitoROS相关氧化应激介导的。循环脂质代谢物，特别是甘油三酯衍生的代谢物的更有利特征，导致晚发性PMW中内皮细胞mitoROS降低。这些发现为晚发性绝经时心血管疾病风险降低的可能机制提供了新的见解。
