© 1999 American Heart Association, Inc.
Original Contributions |
Cooperation Between VEGF and TNF-
Is Necessary for Exposure of Active Tissue Factor on the Surface of Human Endothelial Cells
From the Institute of Pharmacological Sciences, University of Milan, Milan, Italy (M.C., E.T.); the Division of Thrombosis Research, Department of Medicine (P.L.A.G., Y.N.), the Departments of Medicine and Pathology (J.F.), the Ruttenberg Cancer Center (B.M.A.), and The Cardiovascular Institute, Department of Medicine, Mount Sinai School of Medicine (M.T.), New York, NY.
Correspondence to Marina Camera, PhD, Institute of Pharmacological Sciences, University of Milan, Via Balzaretti, 9, 20133 Milan, Italy. E-mail Marina.Camera{at}unimi.it
Abstract—This study was
undertaken to characterize tissue factor (TF) induction, localization,
and functional activity in cultured human umbilical vein
endothelial cells (HUVECs) exposed to recombinant
vascular endothelial growth factor (rVEGF) and
recombinant tumor necrosis factor-
(rTNF-). rVEGF (1 nmol/L) and
rTNF- (500 U/mL) synergistically increased TF mRNA, protein, and
total activity, as measured in cell lysates. To examine surface TF
expression, living cells were treated with antibody to TF and examined
microscopically. Almost no staining was seen in control cells or cells
treated with a single agent. In contrast, cells treated with both
agonists showed intense membrane staining with surface patches,
appearing as buds by confocal microscopy. To determine surface TF
activity, studies were performed using a parallel-plate flow chamber,
which allows detection of factor Xa generation on living cells. rVEGF
and rTNF- induced little surface TF activity (0.032±0.008 and
0.014±0.008 fmol/cm2, respectively). In combination, they
significantly increased TF expression on the cell surface (0.429±0.094
fmol/cm2, P<0.05). These data indicate that
the synergistic effect of rVEGF and rTNF- is necessary to generate
functional TF on the surface of endothelial cells. The
requirement for multiple agonists to expose active TF may serve to
protect endothelial cells from acting as a procoagulant
surface, even under conditions of cell perturbation.
Key Words: endothelium • factor Xa generation • procoagulant activity • cytokines • growth factors
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