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Thromb Res. 2004;114(1):57-65.

Plasminogen activator inhibitor-1 deficiency enhances flow-induced smooth muscle cell migration.

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  • 1Department of Surgery, University of Rochester Medical Center, Box SURG, 601 Elmwood Avenue, Rochester, NY 14642-8410, USA.

Abstract

INTRODUCTION:

We determined the role of smooth muscle cell (SMC)-derived plasminogen activator inhibitor-1 (PAI-1) in the flow-induced SMC migratory response.

MATERIALS AND METHODS:

Wild type (wt) or PAI-1 knockout SMC were cultured in the absence or presence of endothelial cells (EC) under static or pulsatile flow conditions in a perfused culture system. SMC migration was then assessed by Transwell assay.

RESULTS:

Pulsatile flow significantly increased SMC PAI-1 mRNA and protein levels, approximately 4- and 3-fold respectively (n = 4, p < 0.05). In the absence, but not in the presence of EC, pulsatile flow significantly increased ( approximately 2.4-fold) the migration of wt SMC when compared to wt SMC cultured under static conditions. PAI-1 -/-SMC migration was significantly increased under flow conditions as compared to wild-type controls (334 +/- 22% vs. 237 +/- 11%, n = 6, p < 0.05). This flow-induced migration was significantly attenuated, but not completely inhibited, when PAI-1 -/-SMC were cultured in the presence of EC (147 +/- 13%, n = 6, p < 0.05). The flow-induced PAI-1 -/-SMC migratory response was partially inhibited by an anti-urokinase plasminogen activator (uPA) antibody (#1189), and completely inhibited by both 1189 and the matrix metalloproteinase (MMP) inhibitor BB3103. In parallel PAI-1 -/-SMC cells, there was a greater flow-induced increase in proMMP-2 activity as compared to wild-type control cells. Moreover, under both static and flow conditions, tissue inhibitors of matrix metalloproteinases (TIMP)-2 activity was reduced in these PAI-1-deficient cells as compared to wild-type controls.

CONCLUSIONS:

These results suggest that SMC PAI-1 plays a role in limiting flow-induced SMC migration and thus may be an important mechanism for controlling the process of vascular remodelling.

[PubMed - indexed for MEDLINE]
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