Relative contributions of mitochondrial and non-mitochondrial oxidative stress in age-related endothelial dysfunction

BACKGROUND: Increased oxidative stress in older-adults causes microvascular endothelial dysfunction, characterized by reduced nitric oxide (NO) production and bioavailability. However, the specific source(s) of oxidative stress that contribute to microvascular endothelial dysfunction in older adults remain unclear. The present study sought to determine the relative contributions of mitochondrial and non-mitochondrial oxidative stress in age-related cutaneous microvascular endothelial dysfunction. We hypothesized that a) local treatment with mitochondria-specific (mitoTempo) and non-specific (Tempol) antioxidants would similarly improve NO-dependent vasodilation in older adults, and b) chronic supplementation with a mitochondrial antioxidant (MitoQ) would improve NO-dependent vasodilation compared with a placebo. METHODS: In a double-blinded, randomized, cross-over fashion, sixteen older adults (67 ± 3 yrs; 7 M, 8 F) completed 6 weeks of treatment with MitoQ (20mg/day) and a matched placebo. After each six-week treatment period, three intradermal microdialysis fibers were placed in the ventral aspect of the forearm for the local delivery of pharmacological agents. Sites were randomly assigned for treatment with 10mM Tempol (superoxide dismutase mimetic), 1mM mitoTempo (mitochondria-specific superoxide dismutase mimetic), and a vehicle control (Ringer’s). After ~20 min baseline, a standard local heating protocol (42°C) induced cutaneous vasodilation. After observing a stable local heating plateau, 15mM N-Nitro-L-arginine-methyl ester Hydrochloride (L-NAME; NO synthase inhibitor) was perfused at each site to quantify the NO-contribution to the local heating response. Red cell flux was measured at each site by laser-Doppler flowmetry (LDF) and cutaneous vascular conductance (CVC=LDF/MAP) was expressed as a percentage of maximum (%CVCmax; 28mM sodium nitroprusside+43°C). NO-mediated dilation was calculated as the difference between the local heating and L-NAME plateaus (Δ%CVCmax). Non-NO-mediated dilation was calculated as the difference between the L-NAME plateau and baseline. RESULTS: During the placebo visit, Tempol improved the local heating response compared with Ringer’s (76.37 ± 18.99 vs. 51.07 ± 23.36, p = 0.02), but mitoTempo (68.66 ± 30.74, p = 0.25) did not. Likewise, Tempol improved Δ%CVCmax compared with Ringer’s (61.40 ± 15.92 vs. 37.02 ± 20.64, p = 0.01), but mitoTempo (44.36 ± 25.91, p = 0.69) did not. However, mitoTempo improved non-NO-mediated dilation compared with Ringer’s (13.95 ± 16.43 vs. 4.04 ± 6.14; p < 0.01), whereas Tempol did not (7.16 ± 7.55; p = 0.41). There were no significant differences between Tempol or mitoTempo in the magnitude of the local heating response (p = 0.73), Δ%CVCmax (p = 0.14), or non-NO-mediated dilation (p = 0.19). Compared with the placebo visit, MitoQ did not improve the local heating response (p = 0.57), Δ%CVCmax (p = 0.77), or non-NO mediated dilation (p = 0.83). There were no differences in baseline (p = 0.89) or CVCmax among treatments (p = 0.13). CONCLUSIONS: These data suggest that, although mitochondrial oxidative stress may partially contribute, age-related cutaneous microvascular endothelial dysfunction is primarily mediated by non-mitochondria-derived oxidative stress. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.