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(Circulation Research. 2002;90:1122.)
© 2002 American Heart Association, Inc.

Integrative Physiology

Factor Xa Releases Matrix Metalloproteinase-2 (MMP-2) From Human Vascular Smooth Muscle Cells and Stimulates the Conversion of Pro–MMP-2 to MMP-2

Role of MMP-2 in Factor Xa–Induced DNA Synthesis and Matrix Invasion

Bernhard H. Rauch, Ellen Bretschneider, Marina Braun, Karsten Schrör

From the Institut für Pharmakologie und Klinische Pharmakologie (B.H.R., M.B., K.S.), UniversitätsKlinikum Düsseldorf, Heinrich-Heine-Universität, Düsseldorf; and Zentrum für Vaskuläre Biologie und Medizin Erfurt (E.B.), Friedrich-Schiller-Universität Jena, Germany.

Correspondence to Karsten Schrör, Institut für Pharmakologie und Klinische Pharmakologie, Moorenstr. 5, D-40225 Düsseldorf, Germany. E-mail kschroer{at}uni-duesseldorf.de

Pro–matrix metalloproteinase-2 (pro–MMP-2) is expressed in vascular smooth muscle cells (SMCs). We report that activated coagulation factor X (FXa) induces the release of MMP-2 (65 kDa) from human SMCs. In addition, FXa cleaves pro–MMP-2 (72 kDa) into MMP-2. Pro–MMP-2 and MMP-2 were determined by gelatin zymography. MMP-2 was generated in conditioned medium containing pro–MMP-2 in a concentration-dependent fashion by FXa (3 to 100 nmol/L). FX at concentrations up to 300 nmol/L was ineffective. The conversion of pro–MMP-2 to MMP-2 was inhibited by a selective FXa inhibitor (DX-9065a) at 3 to 10 µmol/L. There was a concentration-dependent induction of an intermediate MMP-2 form (68 kDa) in lysates of FXa-treated cells. This indicates that cellular mechanisms are involved in FXa-induced conversion of pro–MMP-2. As a possible biological consequence of MMP-2 activation by FXa, DNA synthesis and matrix invasion of SMCs were determined. Both were stimulated by FXa and inhibited by the selective FXa inhibitor DX-9065a and the MMP inhibitor GM 6001 but not by hirudin or aprotinin. It is concluded that stimulation of SMCs by FXa increases the levels of MMP-2 in the extracellular space and that two different mechanisms are involved: release of active MMP-2 and cleavage of secreted pro–MMP-2. Both might contribute to the mitogenic potency of FXa and FXa-stimulated matrix invasion of SMCs.

Key Words: matrix metalloproteinase-2 • factor Xa • vascular smooth muscle cells • extracellular matrix invasion • mitogenesis

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