Decreased production of collagen Type III in cultured smooth muscle cells from varicose vein patients is due to a degradation by MMPs: possible implication of MMP-3.
An alteration of extracellular matrix is involved in varicose veins. We have previously shown that collagen III production, but not its mRNA expression, is decreased in cultured smooth muscle cells (SMC) from varicose veins, involving an over-production of collagen I. In this study, the mechanisms involved in this collagen III reduction are explored. Steady state levels of collagen III mRNA and its ability to translate a protein were evaluated. Neither stability nor functionality of the alpha1(III) coding mRNA were affected in cells from varicose veins. Potential intracellular degradations of collagen III were investigated with inhibitors of intracellular proteases but the production was unaffected. The level of N-terminal propeptides of collagen III in the extracellular medium was determined and was similar in SMC from control and varicose veins. The stability of collagen III was determined by time-course experiments and a degradation of the protein was observed in cells from varicose veins. The production of collagen III was partially restored in cells from varicose veins in the presence of Marimastat, a matrix metalloproteinase (MMP) inhibitor. The mRNA expression and protein production of MMP3 were increased in cells from varicose veins. Fibronectin, a potential substrate of MMP3, was decreased in SMC from varicose veins. In conclusion, collagen III, and probably fibronectin, are degraded extracellularly in SMC from varicose veins by a mechanism involving MMPs, and maybe MMP3 by a direct or an indirect pathway. The degradation of collagen III and fibronectin may have repercussions for the mechanical properties of the venous wall.
Sansilvestri-Morel
Patricia
P
Division of Angiology, Servier Research Institute, Suresnes, and Department of Cardiovascular Surgery, European Hospital Georges Pompidou, Paris, France.
Rupin
Alain
A
Jullien
Nicolas D
ND
Lembrez
Nathalie
N
Mestries-Dubois
Patricia
P
Fabiani
Jean Noël
JN
Verbeuren
Tony J
TJ
D000368:Aged; D000369:Aged, 80 and over; D002451:Cell Compartmentation; D002478:Cells, Cultured; D024061:Collagen Type III / Q000235:genetics* / Q000378:metabolism; D005110:Extracellular Space / Q000378:metabolism; D005260:Female; D005353:Fibronectins / Q000378:metabolism; D006801:Humans; D008297:Male; D019278:Matrix Metalloproteinase 3 / Q000235:genetics* / Q000378:metabolism*; D008875:Middle Aged; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000378:metabolism / Q000503:physiopathology*; D017395:Plasminogen Activator Inhibitor 1 / Q000378:metabolism; D011347:Procollagen / Q000378:metabolism; D011348:Procollagen N-Endopeptidase / Q000378:metabolism; D011480:Protease Inhibitors / Q000378:metabolism; D014176:Protein Biosynthesis; D020871:RNA Stability; D010959:Tissue Plasminogen Activator / Q000378:metabolism; D014568:Urokinase-Type Plasminogen Activator / Q000378:metabolism; D014648:Varicose Veins / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*
D024061:Collagen Type III; D005353:Fibronectins; D017395:Plasminogen Activator Inhibitor 1; D011347:Procollagen; D011480:Protease Inhibitors; D010959:Tissue Plasminogen Activator; D014568:Urokinase-Type Plasminogen Activator; D011348:Procollagen N-Endopeptidase; D019278:Matrix Metalloproteinase 3