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© The Rockefeller University Press, 0021-9525/1998//233 $5.00
The Journal of Cell Biology, Volume 140, Number 1, , 1998 233-245

Article

Receptor-independent Role of Urokinase-Type Plasminogen Activator in Pericellular Plasmin and Matrix Metalloproteinase Proteolysis during Vascular Wound Healing in Mice



Peter Carmeliet*, Lieve Moons*, Mieke Dewerchin*, Steven Rosenberg{ddagger}, Jean-Marc Herbert§, Florea Lupu||, and Désiré Collen*

* The Center for Transgene Technology and Gene Therapy, Flanders Interuniversity Institute for Biotechnology, Leuven, Belgium; {ddagger} Chiron Corporation, Emeryville, California; § The Haemobiology Research Department, Sanofi Recherche, Toulouse, France; and || The Vascular Biology Laboratory, The Thrombosis Research Institute, London, UK

It has been proposed that the urokinase receptor (u-PAR) is essential for the various biological roles of urokinase-type plasminogen activator (u-PA) in vivo, and that smooth muscle cells require u-PA for migration during arterial neointima formation. The present study was undertaken to evaluate the role of u-PAR during this process in mice with targeted disruption of the u-PAR gene (u-PAR–/–). Surprisingly, u-PAR deficiency did not affect arterial neointima formation, neointimal cell accumulation, or migration of smooth muscle cells. Indeed, topographic analysis of arterial wound healing after electric injury revealed that u-PAR–/– smooth muscle cells, originating from the uninjured borders, migrated over a similar distance and at a similar rate into the necrotic center of the wound as wild-type (u-PAR+/+) smooth muscle cells. In addition, u-PAR deficiency did not impair migration of wounded cultured smooth muscle cells in vitro. There were no genotypic differences in reendothelialization of the vascular wound. The minimal role of u-PAR in smooth muscle cell migration was not because of absent expression, since wild-type smooth muscle cells expressed u-PAR mRNA and functional receptor in vitro and in vivo. Pericellular plasmin proteolysis, evaluated by degradation of 125I-labeled fibrin and activation of zymogen matrix metalloproteinases, was similar for u-PAR–/– and u-PAR+/+ cells. Immunoelectron microscopy of injured arteries in vivo revealed that u-PA was bound on the cell surface of u-PAR+/+ cells, whereas it was present in the pericellular space around u-PAR–/– cells. Taken together, these results suggest that binding of u-PA to u-PAR is not required to provide sufficient pericellular u-PA–mediated plasmin proteolysis to allow cellular migration into a vascular wound.

Abbreviations used in this paper: MMP, matrix metalloproteinase; PA, plasminogen activator; PAI, PA inhibitors; PMA, phorbol myristate acetate; RT, reverse transcriptase; t-PA, tissue-type PA; u-PA, urokinase-type PA.

The work of the London group was supported by the British Heart Foundation.

Address all correspondence to P. Carmeliet, Center for Transgene Technology and Gene Therapy, Flanders Interuniversity Institute for Biotechnology, Campus Gathuisberg, KU Leuven, Herestraat 49, B-3000 Leuven, Belgium. Tel.: 32-16-345772. Fax: 32-16-345990. E-mail: peter.carmeliet{at}med.kuleuven.ac.be


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