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(Circulation Research. 2002;91:861.)
© 2002 American Heart Association, Inc.

Editorials

Targeting Pericellular Proteolysis in Vascular Disease

Michelle P. Bendeck

From the Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.

Correspondence to Dr Michelle P. Bendeck, Associate Professor, Dept of Laboratory Medicine and Pathobiology, University of Toronto, Medical Sciences Bldg., Room 6217, 1 King’s College Circle, Toronto, ON M5S 1A8, Canada. E-mail michelle.bendeck@utoronto.ca

Key Words: plasminogen activator • matrix metalloproteinase • neointimal hyperplasia • cell migration

An extract of the first 250 words of the full text is provided, because this article has no abstract.

Proteolytic enzymes released from smooth muscle cells (SMCs) degrade extracellular matrix proteins, and this is thought to facilitate cell migration and neointimal thickening in restenosis and vein graft disease. The plasminogen activator (PA) and the matrix metalloproteinase (MMP) systems play important roles mediating these processes. In the PA system, tissue-type plasminogen activator (t-PA) and urokinase-type plasminogen activator (u-PA) cleave plasminogen to release plasmin (Figure A). Many components of the PA system including t-PA, u-PA, and the endogenous plasminogen activator inhibitor (PAI-1) are upregulated in diseased blood vessels,¹ and recent studies using mice with targeted gene deletion point to a role for u-PA in mediating neointimal hyperplasia.² u-PA may have a particularly important role in facilitating SMC migration, because it is localized to the cell surface by binding to the u-PA receptor (u-PAR). This potentiates the activity of u-PA by bringing the enzyme into close proximity to its surface-bound plasminogen substrate, permitting plasmin activation within a spatially constrained pericellular environment (Figure A). Plasmin can directly degrade some components of the extracellular matrix and has the potential to activate several of the matrix metalloproteinases including MMP-3, 9, 12, and 13. In fact, there is good evidence that the effects of u-PA/plasmin in tissue remodeling are mediated indirectly via activation of the MMPs.¹

View larger version (16K): [in this window] [in a new window]   Model for the action of TIMP-1.ATF inhibiting both PA/plasmin and MMP activity in the pericellular environment. A, Plasmin generated by either u-PA or t-PA is capable of directly degrading components of the extracellular matrix. Plasmin can . . . [Full Text of this Article]