Urokinase but not tissue plasminogen activator mediates arterial neointima formation in mice.
To define the role of the plasminogen activators (PAs) tissue PA (t-PA) and urokinase PA (u-PA) in vascular wound healing, neointima formation and reendothelialization were evaluated after electric or mechanical arterial injury in mice with a single or combined deficiency of t-PA (t-PA-/-) and/or u-PA (u-PA-/-). In both models, neointima formation and neointimal cell accumulation were reduced in u-PA-/- and in t-PA-/-/u-PA-/- arteries but not in t-PA-/- arteries. The electric injury model was used to characterize the underlying cellular mechanisms. Topographic analysis of vascular wound healing in electrically injured wild-type and t-PA-/- arteries revealed a similar degree of migration of smooth muscle cells from the noninjured borders into the necrotic center. In contrast, in u-PA-/- and t-PA-/-/u-PA-/- arteries, smooth muscle cells accumulated at the uninjured borders but failed to migrate into the necrotic center. Cultured u-PA-/- but not t-PA-/- smooth muscle cells also failed to migrate in vitro after scrape wounding. Proliferation of smooth muscle cells was not affected by PA deficiency. Reendothelialization after electric injury was similar in all genotypes. In situ analysis revealed markedly elevated u-PA zymographic activity, mRNA, and immunoreactivity in smooth muscle cells, endothelial cells, and leukocytes within 1 week after injury, eg, when cells migrated into the wound. Thus, u-PA plays a significant role in vascular wound healing and arterial neointima formation after injury, most likely by affecting cellular migration.
Carmeliet
P
P
Center for Transgene Technology and Gene Therapy, Flanders Interuniversity Institute for Biotechnology, Leuven, Belgium.
Moons
L
L
Herbert
J M
JM
Crawley
J
J
Lupu
F
F
Lijnen
R
R
Collen
D
D
D000818:Animals; D002339:Carotid Arteries / Q000473:pathology* / Q000503:physiopathology*; D002404:Catheterization; D002455:Cell Division; D002465:Cell Movement; D005260:Female; D017353:Gene Deletion; D005786:Gene Expression Regulation; D008297:Male; D051379:Mice; D010959:Tissue Plasminogen Activator / Q000502:physiology*; D017539:Tunica Intima / Q000503:physiopathology*; D014568:Urokinase-Type Plasminogen Activator / Q000502:physiology*
D010959:Tissue Plasminogen Activator; D014568:Urokinase-Type Plasminogen Activator