Excess mitochondrial oxidative stress contributes to vascular endothelial dysfunction in postmenopausal women: possible protection by late-onset menopause
Authors: Darvish Sanna , Murray Kevin , Freeberg Kaitlin , Coppock Mckinley , Seals Douglas , Rossman Matthew 
Published: May 2023

Cardiovascular disease (CVD) risk is increased in estrogen-deficient postmenopausal women (POST-W). Increased CVD risk in POST-W is due, in part, to impaired vascular endothelial function, characterized by lower endothelium-dependent dilation (EDD) compared to premenopausal women (PRE-W). Excess mitochondrial reactive oxygen species (mtROS)-related oxidative stress is thought to contribute to endothelial dysfunction in POST-W due to the loss of estradiol and its associated mitochondrial-protective effects, but whether mtROS is a contributing mechanism to endothelial dysfunction in POST-W is unknown. Additionally, POST-W who transition into menopause late (>55 yrs) (L-POST-W) have lower CVD risk compared to age-matched POST-W who transition at a typical age (45-55 yrs) (N-POST-W). However, it is unknown if lower CVD risk in L-POST-W is associated with higher endothelial function compared to N-POST-W and if this is mediated, in part, by lower mtROS. PURPOSE: To determine 1) if excess mtROS-related oxidative stress contributes to lower EDD in POST-W; 2a) whether EDD is greater in L-POST-W compared to N-POST-W; and, if so, 2b) whether this difference can be explained by lower mtROS in L-POST-W. METHODS & RESULTS: EDD was assessed by brachial artery flow-mediated dilation (FMD) in a reference group of PRE-W (n=17) (mean±SEM; age: 24±1 yrs) and a group of POST-W (n=18) (age: 66±1 yrs). FMD was lower in POST-W vs. PRE-W (5.7±0.8% vs. 8.0±0.6%, p=0.02). After assessment of FMD at baseline, POST-W ingested an acute supratherapeutic dose (160mg) of the mitochondrial-targeted antioxidant MitoQ to reversibly inhibit mtROS, and FMD was assessed 1 hour later. The difference in FMD from baseline with MitoQ was taken as the tonic suppression of EDD by mtROS-related oxidative stress. FMD increased from baseline with MitoQ in POST-W (baseline: 5.7±0.8%; MitoQ: 7.7±0.8%, p<0.0001) such that FMD after MitoQ in POST-W was not different from PRE-W (p=0.74). We next sought to determine if L-POST-W exhibit higher EDD compared to age-matched N-POST-W by separating our cohort based on age at menopause. Baseline FMD in L-POST-W (n=6, 7.7±1.0%) was higher than in N-POST-W (n=11, 4.6±0.7%, p=0.015). FMD increased with MitoQ in N-POST-W (baseline: 4.6±0.7%; MitoQ: 7.0±3.7%, p<0.0001) but not in L-POST-W (baseline: 7.7±1.0%; MitoQ: 8.9±2.7%, p=0.10). CONCLUSION: These findings are the first to show excess mtROS-related oxidative stress contributes to endothelial dysfunction in POST-W. Our observations also suggest that in comparison to N-POST-W, L-POST-W women have better endothelial function, which is partly mediated by lower mtROS. In combination, these findings identify mtROS as a novel mechanism of declines in endothelial function after menopause in women and show that a later age at menopause may be associated with higher endothelial function due, in part, to lower mtROS, which may explain lower CVD risk in women who transition into menopause. FUNDING: NIH K01DK115524 (MJR); R01AG066730 (DRS); T32DK007135 (KOM); F31HL154782 (KAF); NIH/NCATS CTSA UL1 TR002535. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.