The catalytic domain of endogenous urokinase-type plasminogen activator is required for the mitogenic activity of platelet-derived and basic fibroblast growth factors in human vascular smooth muscle cells.
Emerging data suggest that urokinase-type plasminogen activator (UPA), beyond its role in pericellular proteolysis, may also act as a mitogen. We investigated the function of endogenous UPA in mediating the mitogenic effects of platelet-derived growth factor (PDGF) and basic fibroblast growth factor (bFGF) on human vascular smooth muscle cells (SMC). Growth-arrested SMC constitutively expressed UPA, but UPA expression and secretion increased several times upon stimulation with either PDGF or bFGF. Inhibition of endogenous UPA with a polyclonal antibody significantly reduced DNA synthesis and proliferation of PDGF or bFGF stimulated SMC, this effect already being evident when the cells entered S-phase. The proliferative activity of endogenous UPA was dependent on a functional catalytic domain as demonstrated by inhibition experiments with a specific monoclonal antibody (394OA) and p-aminobenzamidine, respectively. In contrast, neither plasmin generation nor binding of UPA to its receptor (CD87) were required for UPA-mediated mitogenic effects. The results demonstrate that endogenous UPA is not only overexpressed in SMC upon stimulation with PDGF/bFGF, but also mediates the mitogenic activity of the growth factors in a catalytic-domain-dependent manner. Specific inhibition of this UPA domain may represent an attractive target for pharmacological interventions in atherogenesis and restenosis after angioplasty.
Padró
Teresa
T
Department of Medicine, Hematology and Oncology, University of Münster, Albert-Schweitzer Strasse 33, D-48129 Münster, Germany.
Mesters
Rolf M
RM
Dankbar
Berno
B
Hintelmann
Heike
H
Bieker
Ralf
R
Kiehl
Michael
M
Berdel
Wolfgang E
WE
Kienast
Joachim
J
D001161:Arteriosclerosis / Q000378:metabolism / Q000503:physiopathology; D047390:Casein Kinase II; D020134:Catalytic Domain / Q000502:physiology*; D002455:Cell Division / Q000187:drug effects / Q000502:physiology*; D002478:Cells, Cultured; D004247:DNA / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005341:Fibrinolysin / Q000096:biosynthesis; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism* / Q000494:pharmacology; D006083:Graft Occlusion, Vascular / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology; D006801:Humans; D006984:Hypertrophy / Q000378:metabolism / Q000503:physiopathology; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000254:growth & development / Q000378:metabolism*; D010982:Platelet-Derived Growth Factor / Q000378:metabolism* / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000378:metabolism; D055293:Receptors, Urokinase Plasminogen Activator; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology; D014568:Urokinase-Type Plasminogen Activator / Q000378:metabolism*
D004791:Enzyme Inhibitors; C524898:PLAUR protein, human; D010982:Platelet-Derived Growth Factor; D011956:Receptors, Cell Surface; D055293:Receptors, Urokinase Plasminogen Activator; D016222:Fibroblast Growth Factor 2; D004247:DNA; D047390:Casein Kinase II; D017346:Protein Serine-Threonine Kinases; D005341:Fibrinolysin; D014568:Urokinase-Type Plasminogen Activator