Fibrinogen binding potentiates FGF-2 but not VEGF induced expression of u-Pa, u-PAR, and PAI-1 in endothelial cells

Abha Sahni, S. K. Sahni, P. J. Simpson-Haidaris, C. W. Francis

Research output: Contribution to journalArticle

22 Scopus citations

Abstract

Endothelial cell responses at sites of injury occur in a fibrin matrix and are regulated by growth factors including those of the FGF and VEGF families. The pericellular proteolytic balance is important in these responses, and FGF-2 and VEGF up-regulate endothelial cell u-PA, u-PAR and PAI-1. Because both VEGF and FGF-2 bind to fibrinogen, we have examined the capacity of fibrinogen to modulate the up-regulation of these proteins by FGF-2 and VEGF. Confluent cultures of endothelial cells were exposed to FGF-2, VEGF, and fibrinogen or to combinations of growth factors with fibrinogen. Changes in mRNA levels of u-PA, u-PAR and PAI-1 were measured by Northern blot. FGF-2 increased u-PA, u-PAR, and PAI-1 mRNA, but there was a significantly greater induction when fibrinogen was added to FGF-2 at all concentrations. The potentiation by fibrinogen was particularly evident at an FGF-2 concentration of 0.1 ng mL-1, which resulted in non-significant change in transcript levels by itself, but significantly increased up to 2.6-fold with fibrinogen. VEGF also increased endothelial cell expression of u-PA, u-PAR and PAI-1, but this effect was not potentiated by fibrinogen. Addition of LM609, a monoclonal antibody to αvβ 3, significantly inhibited induction of u-PA mRNA and activity by fibrinogen - bound FGF-2 compared to FGF-2. A monoclonal antibody to FGFR1 also inhibited u-PA mRNA expression induced by fibrinogen-bound FGF-2. We conclude that fibrinogen increases the capacity of FGF-2, but not of VEGF, to up-regulate u-PA, u-PAR, and PAI-1 in endothelial cells and that fibrinogen-bound FGF-2 requires αvβ3 binding to up-regulate endothelial cell u-PA.

Original languageEnglish (US)
Pages (from-to)1629-1636
Number of pages8
JournalJournal of Thrombosis and Haemostasis
Volume2
Issue number9
DOIs
StatePublished - Sep 1 2004

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Keywords

  • FGF-2
  • Fibrinogen
  • PAI-1
  • u-PA
  • u-PAR

ASJC Scopus subject areas

  • Hematology

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