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Blood, 15 November 2000, Vol. 96, No. 10, pp. 3452-3458
HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY
Binding of factor VIIa to tissue factor on human fibroblasts
leads to activation of phospholipase C and enhanced
PDGF-BB-stimulated chemotaxis
Agneta Siegbahn,
Matilda Johnell,
Charlotte Rorsman,
Mirella Ezban,
Carl-Henrik Heldin, and
Lars Rönnstrand
From the Department of Medical Sciences, Laboratory for
Coagulation Research, Clinical Chemistry, University Hospital, Uppsala,
Sweden; the Ludwig Institute for Cancer Research,
Biomedical Centre, Uppsala, Sweden; and Tissue
Factor/Factor VIIa Research, Health Care Discovery, Novo Nordisk A/S,
Maaloev, Denmark.
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 -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.

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