title: Receptor-independent role of urokinase-type plasminogen activator in pericellular plasmin and matrix metalloproteinase proteolysis during vascular wound healing in mice.
abstract: 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.
authors.affiliation: The Center for Transgene Technology and Gene Therapy, Flanders Interuniversity Institute for Biotechnology, Leuven, Belgium. peter.carmeliet@med.kuleuven.ac.be
authors.forename: P
authors.initials: P
authors.lastname: Carmeliet
authors.forename: L
authors.initials: L
authors.lastname: Moons
authors.forename: M
authors.initials: M
authors.lastname: Dewerchin
authors.forename: S
authors.initials: S
authors.lastname: Rosenberg
authors.forename: J M
authors.initials: JM
authors.lastname: Herbert
authors.forename: F
authors.initials: F
authors.lastname: Lupu
authors.forename: D
authors.initials: D
authors.lastname: Collen
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D002633:Chemotaxis / Q000235:genetics / Q000502:physiology; D005260:Female; D005263:Femoral Artery / Q000166:cytology / Q000293:injuries / Q000502:physiology*; D005341:Fibrinolysin / Q000378:metabolism*; D008297:Male; D008666:Metalloendopeptidases / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D016253:Microscopy, Immunoelectron; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000293:injuries / Q000502:physiology*; D011956:Receptors, Cell Surface / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D055293:Receptors, Urokinase Plasminogen Activator; D012038:Regeneration; D017539:Tunica Intima / Q000166:cytology / Q000293:injuries / Q000502:physiology*; D014568:Urokinase-Type Plasminogen Activator / Q000378:metabolism*; D014945:Wound Healing / Q000235:genetics / Q000502:physiology*
chemical_list: C524899:Plaur protein, mouse; D011956:Receptors, Cell Surface; D055293:Receptors, Urokinase Plasminogen Activator; D005341:Fibrinolysin; D014568:Urokinase-Type Plasminogen Activator; D008666:Metalloendopeptidases