Vasodilatory function in human skeletal muscle feed arteries with advancing age: the role of adropin.

KEY POINTS: The present study aimed to determine the impact of ageing on endogenous adropin levels in human skeletal muscle feed arteries (SMFAs) and the role of adropin in age-related vascular dysfunction. Adropin protein expression falls progressively with advancing age in the human peripheral vasculature. Endothelial-dependent vasodilatation, typically attenuated with age, was strongly correlated with SMFA adropin protein levels. Adropin incubation restored age-related endothelial-dependent vasodilatory dysfunction and increased the phosphorylated endothelial nitric oxide synthase (eNOS)/eNOS ratio in an age-dependent manner in the SMFAs. The role of nitric oxide bioavailability was additionally indicated by NOS blockade ablating both the positive vascular effects of adropin incubation and the relationship between endothelial function and adropin protein expression. Additional evidence of a mechanistic link between declining adropin and age-related endothelial dysfunction was documented by a progressively increasing magnitude of effect of adropin-induced eNOS-mediated vasodilatation with ageing. Adropin appears to be a novel therapeutic target for facilitating the restoration of endothelial function with ageing. ABSTRACT: The present study aimed to determine the impact of advancing age on endogenous adropin levels in human skeletal muscle feed arteries (SMFAs) and the role of adropin in age-related vascular dysfunction. Adropin protein expression and vasodilatory capacity was assesed in SMFAs from Young (27 ± 2 years, n = 10), Middle Aged (54 ± 2 years, n = 10) and Old (75 ± 2 years, n = 16) subjects. Endothelial-dependent vasodilatation, with and without adropin incubation, was assessed in response to flow-induced shear stress and ACh. Both SMFA adropin protein expression and endothelial-dependent vasodilatory function exhibited a progressive, age-related, reduction (Flow: Y: 65 ± 3%; Middle Aged: 36 ± 3%; Old: 15 ± 2%; ACh: Young: 63 ± 2%, Middle Aged: 34 ± 3%; Old: 23 ± 3%, P < 0.05). There was a strong positive correlation between SMFA adropin protein expression and both flow (r = 0.81, P < 0.05) and ACh (r = 0.78, P < 0.05). Adropin incubation in the Middle Aged and Old SMFAs restored the vasodilatory response to flow (Middle Aged + Adropin: 59 ± 3%; Old + Adropin: 47 ± 3%, P < 0.05) and ACh (Middle Aged + Adropin: 59 ± 3%; Old + Adropin: 49 ± 2%, P < 0.05). A mechanistic link between adropin and nitric oxide (NO) biovavailabilty was supported by (i) increased phosphorylated endothelial NO synthase (eNOS)/eNOS protein expression with adropin incubation only in the Middle Aged and Old SMFAs; (ii) eNOS blockade ablating both the positive vascular effects of adropin incubation and the relationship between endothelial function and adropin protein expression and (iii) a progressive increase in the magnitude of effect of adropin-induced eNOS-mediated vasodilatation with advancing age. Adropin could be a novel therapeutic target for facilitating the restoration of endothelial function via increased NO bioavailability, with advancing age.