Arterial stiffening with ageing is associated with transforming growth factor-β1-related changes in adventitial collagen: reversal by aerobic exercise

We tested the hypothesis that carotid artery stiffening with ageing is associated with transforming growth factor-beta 1 (TGF-beta 1)-related increases in adventitial collagen and reductions in medial elastin, which would be reversed by voluntary aerobic exercise. Ex vivo carotid artery incremental stiffness was greater in old (29-32 months, n = 11) vs. young (4-7 months, n = 8) cage control B6D2F1 mice (8.84 +/- 1.80 vs. 4.54 +/- 1.18 AU, P < 0.05), and was associated with selective increases in collagen I and III and TGF-beta 1 protein expression in the adventitia (P < 0.05), related to an increase in smooth muscle alpha-actin (SM alpha A) (myofibroblast phenotype) (P < 0.05). In cultured adventitial fibroblasts, TGF-beta 1 induced increases in superoxide and collagen I protein (P < 0.05), which were inhibited by Tempol, a superoxide dismutase. Medial elastin was reduced with ageing, accompanied by decreases in the pro-synthetic elastin enzyme, lysyl oxidase, and increases in the elastin-degrading enzyme, matrix metalloproteinase 2. Fibronectin was unchanged with ageing, but there was a small increase in calcification (P < 0.05). Increased incremental stiffness in old mice was completely reversed (3.98 +/- 0.34 AU, n = 5) by 10-14 weeks of modest voluntary wheel running (1.13 +/- 0.29 km day-1), whereas greater voluntary wheel running (10.62 +/- 0.49 km day-1) had no effect on young mice. The amelioration of carotid artery stiffness by wheel running in old mice was associated with reductions in collagen I and III and TGF-beta 1, partial reversal of the myofibroblast phenotype (reduced SM alpha A) and reduced calcification (all P < 0.05 vs. old controls), whereas elastin and its modulating enzymes were unaffected. Adventitial TGF-beta 1-related oxidative stress may play a key role in collagen deposition and large elastic artery stiffening with ageing and the efficacious effects of voluntary aerobic exercise.