Relative contributions of mitochondrial and nonmitochondrial oxidative stress in age-related cutaneous microvascular endothelial dysfunction.

Aging is associated with oxidative-stress-induced endothelial dysfunction, characterized by reduced nitric oxide (NO) signaling. The present study evaluated the contributions of mitochondrial- and nonmitochondrial oxidative stress in age-related endothelial dysfunction. Three intradermal microdialysis fibers were placed in the forearm for local delivery of pharmacological agents (10 mM Tempol, 1 mM MitoTempo, Ringer's vehicle control) to the cutaneous microvasculature in 15 older (67 ± 3 yr; 7 M and 8 F) adults. After ∼20 min baseline, local heating (42°C) induced cutaneous vasodilation, and perfusion of a NO synthase inhibitor (15 mM N-nitro-l-arginine-methyl ester hydrochloride) allowed quantification of the NO- and non-NO contributions to the local heating response. Red cell flux was measured at each site by laser-Doppler flowmetry (LDF), and cutaneous vascular conductance (CVC = LDF/mean arterial pressure) was expressed as a percentage of maximum (%CVCmax; 28 mM sodium nitroprusside + 43°C). Tempol improved the local heating response compared with Ringer's (76.37 ± 18.99 vs. 51.07 ± 23.36, P = 0.02), but MitoTempo (P = 0.25) did not. Likewise, Tempol improved the NO contribution to the response compared with Ringer's (61.40 ± 15.92 vs. 37.02 ± 20.64, P = 0.01), but MitoTempo (P = 0.69) did not. Conversely, MitoTempo increased the non-NO-mediated component of the response compared with Ringer's (13.95 ± 16.43 vs. 4.04 ± 6.14; P < 0.01), but Tempol did not (P = 0.41). There were no differences between Tempol and MitoTempo (P ≥ 0.14). These data suggest that, although mitochondrial oxidative stress may contribute, a considerable portion of the oxidative stress underlying age-related endothelial dysfunction is derived outside of the mitochondria.NEW & NOTEWORTHY Age-related declines in nitric oxide-mediated cutaneous microvascular function are due, at least in part, to increased oxidative stress. However, the specific sources of oxidative stress that contribute to microvascular endothelial dysfunction with aging remain unclear. Here, we demonstrate that, although mitochondrial oxidative stress may contribute, a considerable portion of the oxidative stress underlying age-related endothelial dysfunction is derived outside of the mitochondria.