ACIDIC AND BASIC FIBROBLAST GROWTH-FACTORS SUPPRESS TRANSCRIPTIONAL ACTIVATION OF TISSUE FACTOR AND OTHER INFLAMMATORY GENES IN ENDOTHELIAL-CELLS

Tissue factor (TF) is a transmembrane receptor that serves as a cofact or for factor VIIa and initiates the extrinsic pathway of blood coagul ation. Under normal physiological conditions, TF is expressed in extra vascular and perivascular cells but not in vascular endothelial cells and monocytes. TF can be induced in these cells by inflammatory regula tors and other stimulators, such as LPS, thrombin, oxidized lipoprotei ns, and certain growth factors. An earlier study showed that growing p rimary cultures of human umbilical vein endothelial cells (HUVECs) wit h endothelial cell growth supplement (EGGS) and heparin had impaired t he ability of monolayers to express surface membrane TF activity after perturbation. The mechanism by which EGGS suppressed TF activity was not known. In the present study, we investigated the effect of recombi nant acidic and basic fibroblast growth factors (aFGF and bFGF) on the induction of TF in a HUVEC cell line and a fibroblast cell line. Both aFGF and bFGF suppressed the phorbol myristate acetate-induced expres sion of TF in endothelial cells but not the serum-induced expression o f TF in fibroblast cells. Diminished expression of the cell surface TF activity observed in endothelial cells grown with aFGF or bFGF was du e to the accumulation of a lower number of TF mRNA transcripts. TF mRN A stability was not altered in HUVECs grown with aFGF or bFGF. Nuclear run-on experiments revealed that the transcription of TF and several other genes that play an important role in inflammation and angiogenes is was reduced in the endothelial cells that were cultured with aFGF o r bFGF. The diminished expression of TF may be part of a generalized r esponse of endothelial cells to FGF that facilitates migration of endo thelial cells during angiogenesis.