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Binding of factor VIIa to tissue factor on human fibroblasts leads to activation of phospholipase C and enhanced PDGF-BB-stimulated chemotaxis

In English

Författare

  • Agneta Siegbahn
  • Matilda Johnell
  • Charlotte Rorsman
  • Mirella Ezban
  • Carl-Henrik Heldin
  • Lars Rönnstrand

Summary, in English

Tissue factor (TF) is the cellular receptor for factor FVIIa (FVIIa), and the complex is the principal initiator of blood coagulation. The effects of FVIIa binding to TF on cell migration and signal transduction of human fibroblasts, which express high amounts of TF, were studied. Fibroblasts incubated with FVIIa migrated toward a concentration gradient of PDGF-BB at approximately 100 times lower concentration than do fibroblasts not ligated with FVIIa. Anti-TF antibodies inhibited the increase in chemotaxis induced by FVIIa/TF. Moreover, a pronounced suppression of chemotaxis induced by PDGF-BB was observed with active site-inhibited FVIIa (FFR-FVIIa). The possibility that hyperchemotaxis was induced by a putative generation of FXa and thrombin activity was excluded. FVIIa/TF did not induce increased levels of PDGF beta-receptors on the cell surface. Thus, the hyperchemotaxis was not a result of this mechanism. FVIIa induced the production of inositol-1,4, 5-trisphosphate to the same extent as PDGF-BB; the effects of FVIIa and PDGF-BB were additive. FFR-FVIIa did not induce any release of inositol-1,4,5,-trisphosphate. Thus, binding of catalytically active FVIIa to TF can, independent of coagulation, modulate cellular responses, such as chemotaxis.

Publiceringsår

2000

Språk

Engelska

Sidor

3452-3458

Publikation/Tidskrift/Serie

Blood

Volym

96

Issue

10

Dokumenttyp

Artikel i tidskrift

Förlag

American Society of Hematology

Ämne

  • Medicinal Chemistry

Nyckelord

  • CulturedChemotaxis/*drug effectsDose-Response Relationship
  • DrugEndothelium
  • Vascular/drug effectsEnzyme ActivationFactor VIIa/*metabolism/pharmacologyFactor Xa/pharmacologyFibroblasts/chemistry/*metabolismHumansIsoenzymes/drug effects/metabolismMuscle
  • Amino Acid Chloromethyl Ketones/pharmacologyBinding SitesCells
  • Smooth
  • Vascular/cytologyPhospholipase C gammaPhosphorylation/drug effectsPlatelet-Derived Growth Factor/*pharmacologyProtein BindingSerine Proteinase Inhibitors/pharmacologySignal TransductionThrombin/pharmacologyThromboplastin/*metabolismType C Phospholipases/drug effects/*metabolism

Status

Published

ISBN/ISSN/Övrigt

  • ISSN: 1528-0020