Vasodilatory and vascular mitochondrial respiratory function with advancing age: Evidence of a free radically mediated link in the human vasculature

Recognizing the age-related decline in skeletal muscle feed artery (SMFA) vasodilatory function, this study examined the link between vasodilatory and mitochondrial respiratory function in the human vasculature. Twenty-four SMFAs were harvested from young (35 ± 6 yr, n = 9) and old (71 ± 9 yr, n = 15) subjects. Vasodilation in SMFAs was assessed, by pressure myography, in response to flowinduced shear stress, acetylcholine (ACh), and sodium nitroprusside (SNP) while mitochondrial respiration was measured, by respirometry, in permeabilized SMFAs. Endothelium-dependent vasodilation was significantly attenuated in the old, induced by both flow (young: 92 ± 3, old: 45 ± 4%) and ACh (young: 92 ± 3, old: 54 ± 5%), with no significant difference in endothelium-independent vasodilation. Complex I and I + II state 3 respiration was significantly lower in the old (CI young: 10.1 ± 0.8, old: 7.0 ± 0.4 pmol·s^-1·mg^-1; CI + II young: 12.3 ± 0.6, old: 7.6 ± 0.4 pmol·s^-1·mg^-1). The respiratory control ratio (RCR) was also significantly attenuated in the old (young: 2.2 ± 0.1, old: 1.1 ± 0.1). Furthermore, state 3 (CI + II) and 4 respiration, as well as RCR, were significantly correlated (r = 0.49- 0.86) with endothelium-dependent, but not endothelium-independent, function. Finally, the direct intervention with mitochondrial-targeted antioxidant (MitoQ) significantly improved endothelium-dependent vasodilation in the old but not in the young. Thus, the age-related decline in vasodilatory function is linked to attenuated vascular mitochondrial respiratory function, likely by augmented free radicals. NEW & NOTEWORTHY In human skeletal muscle feed arteries, the well-recognized age-related fall in endothelium-dependent vasodilatory function is strongly linked to a concomitant fall in vascular mitochondrial respiratory function. The direct intervention with the mitochondrial-targeted antioxidant restored vasodilatory function in the old but not in the young, supporting the concept that exacerbated mitochondrial-derived free radical production is linked to age-related vasodilatory dysfunction. Age-related vasodilatory dysfunction in humans is linked to attenuated vascular mitochondrial respiratory function, likely a consequence of augmented free radical production.