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-β1 (TGF-β1)-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-β1 protein expression in the adventitia (P < 0.05), related to an increase in smooth muscle α-actin (SMαA) (myofibroblast phenotype) (P < 0.05). In cultured adventitial fibroblasts, TGF-β1 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-β1, partial reversal of the myofibroblast phenotype (reduced SMαA) and reduced calcification (all P < 0.05 vs. old controls), whereas elastin and its modulating enzymes were unaffected. Adventitial TGF-β1-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.
Fleenor
Bradley S
BS
Department of Integrative Physiology, University of Colorado, Boulder, CO 80309, USA. bradley.fleenor@colorado.edu
Marshall
Kurt D
KD
Durrant
Jessica R
JR
Lesniewski
Lisa A
LA
Seals
Douglas R
DR
D000375:Aging / Q000378:metabolism* / Q000473:pathology; D000704:Analysis of Variance; D000818:Animals; D002340:Carotid Artery Diseases / Q000378:metabolism* / Q000473:pathology; D002478:Cells, Cultured; D003094:Collagen / Q000378:metabolism*; D003238:Connective Tissue / Q000378:metabolism / Q000473:pathology; D003497:Cyclic N-Oxides / Q000494:pharmacology; D004549:Elastin / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D005353:Fibronectins / Q000378:metabolism; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D051379:Mice; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D010805:Physical Conditioning, Animal / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013113:Spin Labels; D013481:Superoxides / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000378:metabolism* / Q000494:pharmacology
D003497:Cyclic N-Oxides; D005353:Fibronectins; D013113:Spin Labels; D053773:Transforming Growth Factor beta1; D013481:Superoxides; D003094:Collagen; D004549:Elastin; D020778:Matrix Metalloproteinase 2; C001803:tempol
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