Copyright © 2004, European Society of Cardiology
MMP-9 regulates both positively and negatively collagen gel contraction
A nonproteolytic function of MMP-9
aDivision of Vascular Surgery, Department of Surgery, University of Washington, Seattle, WA, USA
bLaboratory of Connective Tissues Biology, University of Liège, Belgium
cDepartment of Cardiovascular Surgery, University of Liège, Belgium
* Corresponding author. University of Liège, Laboratory of Connective Tissues Biology, University of Liège, Belgium. Tel.: +32 4 366 24 59; fax: 32 4 366 24 57. Email address: Olivier.Defawe{at}ulg.ac.be
Objective: 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.
Methods: 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 µg/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.
Results: 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 (
100 ng/ml) inhibited contraction. The addition of BB94 and TIMP-1 did not alter the inhibitory or stimulatory effect of MMP-9.
Conclusions: 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.
KEYWORDS Matrix metalloproteinase-9; Contraction; Rat; Smooth muscle cell; Remodeling
Time for primary review 21 days
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