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

Abstract

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 flow-induced 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.

Targeting mitochondrial fitness as a strategy for healthy vascular aging

“…Excessive mtROS and activation of p66 SHC in the face of reduced or unchanged abundance of MnSOD have been observed in vascular tissues from aged rodents (Figure 3) with corresponding impairments in vascular function [111,112], decreased mitophagy, evidence of reduced mitochondrial quality control [112,113], and greater susceptibility to acute mitochondrial stress [111,113,114]. In humans, expression of MnSOD is lower in vascular endothelial cells obtained by endovascular biopsies from older adults with impaired FMD compared with a young adult reference group [115], and impaired mitochondrial bioenergetics, elevated mtROS and impairments in EDD have been observed in biopsied arterial segments from older vs. young adults [116,117]. More direct evidence for excessive mtROS-mediated suppression of vascular function with primary aging comes from studies in which acute scavenging of mtROS ex vivo in arteries from old mice and older adult humans or in vivo (humans) with the mitochondria-targeted antioxidant MitoQ reverses age-related endothelial dysfunction [111,117,118].…”

Acute mitochondrial antioxidant intake improves endothelial function, antioxidant enzyme activity, and exercise tolerance in patients with peripheral artery disease

“…MitoQ has demonstrated great success in a clinical trial involving healthy middle-aged and older adults, which produced reductions in arterial stiffness, oxidative stress, and improvements in endothelial function (46). We have also previously demonstrated that acute ex vivo treatment with MitoQ can restore age-related endothelial dysfunction in skeletal muscle feed arteries from older adults (72 Ϯ 5 yr) (38) and that this age-related impairment is likely augmented by increased mitochondrial ROS production (36). However, to our knowledge, the impacts of MitoQ on vascular function in patients with PAD in vivo have not been previously investigated.…”

Acute effects of MitoQ on vascular endothelial function are influenced by cardiorespiratory fitness and baseline FMD in middle‐aged and older adults

“…FMD BA <6%) over 6 weeks (Rossman et al, 2018). Furthermore, a single dose (80 mg) of MitoQ improves both brachial and popliteal artery FMD by +2.6 and 3.3% (absolute), respectively, in peripheral artery disease patients (Park et al, 2020). This is clinically relevant as an ∼1% increase in FMD BA decreases CVD-related mortality by ∼13% (Inaba et al, 2010).…”

“…change) in FMD BA with MitoQ was inversely correlated with baseline CRF, suggesting that an underlying mechanism by which higher CRF contributes to enhanced FMD BA in MA/O adults may be attributable, in part, to greater management of mtROS. Improvements in vascular endothelial function with MitoQ are due to lower mtROS and increased mitochondria antioxidant capacity in experimental animal models and in the skeletal muscle feed arteries of humans (Gioscia-Ryan et al, 2014;Park et al, 2018;Park, Kwon et al, 2020). Inhibition of mtROS with MitoQ either acutely (ex vivo) (Gioscia-Ryan et al, 2014) or chronically (in vivo) (Rossman et al, 2018) abolishes the age-related reduction in endothelial function by restoring NO bioavailability and reducing oxidative stress.…”