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

Tissue factor (TF) is the cellular receptor for factor FVIIa (FVIIa), and t he complex is the principal initiator of blood coagulation. The effects of FVIIa binding to TF on cell migration and signal transduction of human fibr oblasts, which express high amounts of TF, were studied. Fibroblasts incuba ted with FVIIa migrated toward a concentration gradient of PDGF-BB at appro ximately 100 times lower concentration than do fibroblasts not ligated with FVIIa. Anti-TF antibodies inhibited the crease in chemotaxis induced by FV IIa/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 throm bin activity was excluded. FVIIa/TF did not induce increased levels of PDGF beta -receptors on the cell surface. Thus, the hyperchemotaxis was not a r esult of this mechanism. FVIIa induced the production of inositol-1,4,5-tri sphosphate 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,-tris phosphate. Thus, binding of catalytically active FVIIa to TF can, independe nt of coagulation, modulate cellular responses, such as chemotaxis. (C) 200 0 by The American Society of Hematology.