MMP-9 regulates both positively and negatively collagen gel contraction A nonproteolytic function of MMP-9

• Published in: Cardiovascular research Vol. 66; no. 2; pp. 402 - 409
• Main Authors: DEFAWE, Olivier D, KENAGY, Richard D, CHOI, Chun, WAN, Samuel Y. C, DEROANNE, Christophe, NUSGENS, Betty, SAKALIHASAN, Natzi, COLIGE, Alain, CLOWES, Alexander W
• Format: Journal Article Web Resource
• Language: English
• Published: Oxford Oxford University Press 01.05.2005; Elsevier Science
• Subjects: Animals; Aorta; Biological and medical sciences; Cardiology. Vascular system; Cardiovascular & respiratory systems; Cell Culture Techniques; Cell Proliferation - drug effects; Chirurgie; Collagen; contraction; Dose-Response Relationship, Drug; Gels; Human health sciences; Matrix Metalloproteinase 9 - physiology; Matrix Metalloproteinase Inhibitors; matrix metalloproteinase-9; Medical sciences; Muscle, Smooth, Vascular - drug effects; Phenylalanine - analogs & derivatives; Phenylalanine - pharmacology; Phenylalanine/analogs & derivatives/pharmacology; Rats; Rats, Inbred F344; remodeling; Sciences de la santé humaine; smooth muscle cell; Surgery; Systèmes cardiovasculaire & respiratoire; Thiophenes - pharmacology; Tissue Inhibitor of Metalloproteinase-1 - pharmacology; Vasoconstriction - drug effects; Smooth muscle cell; Rat; Enzyme; Rodentia; Metalloendopeptidases; Smooth muscle; Remodeling; Contraction; Gelatinase B; Vascular remodeling; Matrix metalloproteinase-9; Peptidases; Vertebrata; Regulation(control); Mammalia; Animal; Collagen; Hydrolases; Cell
• ISSN: 0008-6363; 1755-3245
• DOI: 10.1016/j.cardiores.2004.11.025

Constrictive remodeling accounts for lumen loss in postangioplasty restenosis. Matrix metalloproteinase-9 (MMP-9) has been shown to prevent constrictive remodeling in vivo. To investigate potential mechanisms for this observation, we investigated the role of MMP-9 in smooth muscle cell (SMC)-mediated collagen gel contraction, an in vitro model of constrictive remodeling. Fischer rat SMCs were stably transfected with a construct-expressing rat-MMP-9 under the control of a tetracycline (Tet)-off promoter. SMCs were seeded in type I collagen gels (2.4 mg/ml) in the presence or not of tetracycline (1 microg/ml), and gel contraction was defined as the percentage of retraction of the collagen gel. The depletion of MMP-9 was obtained by using siRNA targeting MMP-9 mRNA or a blocking antibody. Gel contraction was significantly reduced at all times when MMP-9 was overexpressed (Tet-) as compared with the control condition (Tet+). However, MMP-9 depletion of control (Tet+) SMCs (using siRNA or antibody) also inhibited gel contraction. To resolve the apparent discrepancy and determine if MMP-9 exerts a dose-dependent biphasic effect on gel contraction, conditioned medium and purified rat-MMP-9 were prepared. Gel contraction was significantly increased by addition of 0.8 ng/ml of MMP-9, while high concentrations of MMP-9 (> or =100 ng/ml) inhibited contraction. The addition of BB94 and TIMP-1 did not alter the inhibitory or stimulatory effect of MMP-9. Our data suggest that MMP-9, independent of its proteolytic function, has a biphasic effect on SMC-mediated collagen gel contraction. Understanding the different roles of MMP-9 should allow the development of better therapeutic strategies for restenotic vascular disease.