The Influence of Exogenous Tissue Factor on the Regulators of Proliferation and Apoptosis in Endothelial Cells

Abstract

Background: The exposure of tissue factor (TF) at the site of injury or trauma is a rapid process that leads to the initiation of blood coagulation as well as homeostatic processes giving rise to vascular repair. Aims and Methods: By exposing human endothelial cells to combinations of exogenous TF and factor VIIa (FVIIa) in serum-free medium, the influence of TF concentrations on cellular proliferation and apoptosis was investigated. Results: Lower concentrations of TF resulted in increased cellular proliferation as well as upregulation of cyclin D1, downregulation of p21 and p27 and induction of tube formation in vitro. Conversely, incubation with higher concentrations of TF resulted in the activation of caspase-3, expression of p53 and Bax, translocation of p53 into the nucleus and induction of DNA fragmentation. Incubation of the cells with TF/FVIIa led to a lower proliferation rate with additional upregulation in p27. Conclusions: TF seems to have a bifunctional role in determining the fate of endothelial cells, depending on the concentration and the interactions of this protein. The release of TF in the locality of the injured tissue makes this protein an ideal factor for ascertaining the level of injury and determining the fate of the cells.

Influence of Exogenous Tissue Factor on Estrogen Receptorα Expression in Breast Cancer Cells: Involvement of β1-Integrin, PAR2, and Mitogen-Activated Protein Kinase Activation

“…In contrast, in the absence of estradiol, a low concentration of rTF (1.3 pg/mL) was proliferative, whereas 13 pg/mL rTF was antiproliferative, a phenomenon also observed previously in endothelial cells (14). Interestingly, the activities of both PAR2 and h 1 -integrin seem to be prerequisite for the ability of rTF to suppress estradiol-mediated cell proliferation (Fig.…”

“…Neutralization of the labeled rTF using a polyclonal anti-TF antibody or competition with excess unlabeled rTF abolished the binding of fluoresceinlabeled rTF (Table 1). We have shown previously that rTF binds to the surface of endothelial cells (11,14), which possibly occurs through binding to putative cell receptors capable of interacting with TF (16). Furthermore, rTF appeared to be focused at particular points on the cell membrane as reported previously for endogenous TF (17), suggesting an interaction with specific cell surface proteins also localized to these points.…”

Angiogenic Microvascular Endothelial Cells Release Microparticles Rich in Tissue Factor That Promotes Postischemic Collateral Vessel Formation

“…It has been described that exogenous TF induces several cellular effects, such as the induction of proliferation, migration, and finally tube formation. 44,45 Our results shown that the proangiogenic activated mECs are able to release TF-bearing mEMPs, which drive other mECs and pericytes to increase new vessel formation.…”

Induction of Endothelial Cell Proliferation by Recombinant and Microparticle-Tissue Factor Involves β1-Integrin and Extracellular Signal Regulated Kinase Activation

“…4 Furthermore, it has been shown that incubation of endothelial cells (EC) with recombinant TF alone induces cellular proliferation, together with an associated upregulation of cyclin D1 expression in these cells. 7 Recently, a number of reports have demonstrated the ability of TF to interact with cell surface integrins, 8 -11 resulting in diverse cellular outcomes, including the activation of cell signaling pathways, cell migration, and capillary tube formation. 8,9,11 The binding of cell surface TF to ␤1-integrin, ␣3-integrin, and ␣6-integrin on endothelial cells was shown to require FVIIa, 9 whereas binding of alternatively spliced TF (asTF) to ␣v␤3-integrin and ␣6␤1-integrin was shown to be independent of FVIIa.…”

“…Moreover, it was demonstrated that this form of TF interacts with the cell surface. 7,10,21 This study is an attempt to further elucidate the mechanisms by which exogenous TF induces endothelial cell proliferation. Throughout this investigation, 2 forms of "exogenous" TF, lipidated recombinant TF and TF-containing cell-derived microparticles, have been used at concentrations of TF corresponding to those found in healthy individuals (5 to 10 pmol/L) or in plasma of patients with cardiovascular disease (50 to 200 pmol/L).…”