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Molecular and Cellular Biology, March 1999, p. 2032-2043, Vol. 19, No. 3
Centro de Biología Molecular Severo
Ochoa,
Received 25 June 1998/Returned for modification 11 September
1998/Accepted 12 November 1998
Vascular endothelial growth factor (VEGF) is a potent angiogenic
inducer that stimulates the expression of tissue factor (TF), the major
cellular initiator of blood coagulation. Here we show that signaling
triggered by VEGF induced DNA-binding and transcriptional activities of
nuclear factor of activated T cells (NFAT) and AP-1 in human umbilical
vein endothelial cells (HUVECs). VEGF also induced TF mRNA expression
and gene promoter activation by a cyclosporin A (CsA)-sensitive
mechanism. As in lymphoid cells, NFAT was dephosphorylated and
translocated to the nucleus upon activation of HUVECs, and these
processes were blocked by CsA. NFAT was involved in the VEGF-mediated
TF promoter activation as evidenced by cotransfection experiments with
a dominant negative version of NFAT and site-directed mutagenesis of a
newly identified NFAT site within the TF promoter that overlaps with a
previously identified
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.
Vascular Endothelial Growth Factor Activates
Nuclear Factor of Activated T Cells in Human Endothelial Cells: a
Role for Tissue Factor Gene Expression
B-like site. Strikingly, this site bound
exclusively NFAT not only from nuclear extracts of HUVECs activated by
VEGF, a stimulus that failed to induce NF-
B-binding activity, but
also from extracts of cells activated with phorbol esters and calcium
ionophore, a combination of stimuli that triggered the simultaneous
activation of NFAT and NF-
B. These results implicate NFAT in the
regulation of endothelial genes by physiological means and shed light
on the mechanisms that switch on the gene expression program induced by
VEGF and those regulating TF gene expression.
*
Corresponding author. Mailing address: Centro de
Biología Molecular Severo Ochoa, Consejo Superior de
Investigaciones Científicas (CSIC)-Universidad Autónoma
de Madrid. Facultad de Ciencias, Cantoblanco, Madrid 28049, Spain.
Phone: 34-91-397-4252. Fax: 34-91-397-4799. E-mail:
jmredondo{at}cbm.uam.es.
Molecular and Cellular Biology, March 1999, p. 2032-2043, Vol. 19, No. 3
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.
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