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.
J Cell Sci
; 115(Pt 9): 1961-71, 2002 May 01.
Article
em En
| MEDLINE
| ID: mdl-11956327
ABSTRACT
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.
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Base de dados:
MEDLINE
Assunto principal:
Fator de Crescimento Derivado de Plaquetas
/
Ativador de Plasminogênio Tipo Uroquinase
/
Divisão Celular
/
Fator 2 de Crescimento de Fibroblastos
/
Domínio Catalítico
/
Músculo Liso Vascular
Tipo de estudo:
Etiology_studies
Limite:
Humans
Idioma:
En
Ano de publicação:
2002
Tipo de documento:
Article