Sequential activation of matrix metalloproteinase 9 and transforming growth factor beta in arterial elastocalcinosis.
OBJECTIVE
Isolated systolic hypertension is associated with increased elastase activity, vascular calcification, and vascular stiffness. We sought to determine the importance of elastase activity and matrix degradation in the development of elastocalcinosis.


RESULTS
Elastocalcinosis was induced in vivo and ex vivo using warfarin. Hemodynamic parameters, calcium deposition, elastin degradation, transforming growth factor (TGF)-beta signaling, and elastase activity were evaluated at different time points in the in vivo model. Metalloproteinases, serine proteases, and cysteine proteases were blocked to measure their relative implication in elastin degradation. Gradual elastocalcinosis was obtained, and paralleled the elastin degradation pattern. Matrix metalloproteinase (MMP)-9 activity was increased at 5 days of warfarin treatment, whereas TGF-beta signaling was increased at 7 days. Calcification was significantly elevated after 21 days. Blocking metalloproteinases activation with doxycycline and TGF-beta signaling with SB-431542 were able to prevent calcification.


CONCLUSIONS
Early MMP-9 activation precedes the increase of TGF-beta signaling, and overt vascular elastocalcinosis and stiffness. Modulation of matrix degradation could represent a novel therapeutic avenue to prevent the gradual age-related stiffening of large arteries, leading to isolated systolic hypertension.
Bouvet
Céline
C
Faculty of Pharmacy, Université de Montréal, Québec, Canada.
Moreau
Simon
S
Blanchette
Joannie
J
de Blois
Denis
D
Moreau
Pierre
P
D000818:Animals; D001012:Aorta, Abdominal / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D002114:Calcinosis / Q000139:chemically induced / Q000378:metabolism*; D003094:Collagen / Q000378:metabolism; D004195:Disease Models, Animal; D017886:Durapatite / Q000378:metabolism; D004549:Elastin / Q000378:metabolism; D005263:Femoral Artery / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D053495:Osteopontin / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000502:physiology; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D014652:Vascular Diseases / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D014859:Warfarin
D016212:Transforming Growth Factor beta; D053495:Osteopontin; D014859:Warfarin; D003094:Collagen; D004549:Elastin; D017886:Durapatite; D020780:Matrix Metalloproteinase 9