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Blood, Vol. 94 No. 2 (July 15), 1999:
pp. 579-586
Regulation of Tissue Factor Pathway Inhibitor Expression in Smooth
Muscle Cells
Usha R. Pendurthi,
L. Vijaya Mohan Rao,
J. Todd Williams, and
Steven Idell
From the Departments of Molecular Biology, Biochemistry and Medical
Specialties, The University of Texas Health Center at Tyler, Tyler, TX.
Tissue factor pathway inhibitor (TFPI) is the primary physiological
inhibitor that regulates tissue factor-induced blood coagulation. TFPI
is thought to be synthesized, in vivo, primarily by microvascular endothelial cells. Little is known about how TFPI is regulated under
pathophysiological conditions. In this study, we determined mechanisms
by which TFPI expression is regulated by human pulmonary artery smooth
muscle cells (PASMC), because these cells contribute to remodeling of
the pulmonary vasculature in disease. PASMC in culture constitutively
synthesize and secrete TFPI. Exposure of PASMC to phorbol myristate
acetate, lipopolysaccharide, tumor necrosis factor  , thrombin,
interleukin-1, and transforming growth factor- had no significant
effect on expression of TFPI by PASMC. By contrast, treatment of PASMC
with serum and basic fibroblast growth factor (bFGF)/heparin markedly
upregulated the expression of TFPI activity and antigen. On Western
blot analysis, a protein consistent with full-length TFPI (42 kD) was
identified in the conditioned media of PASMC, and the levels of the
protein were much higher in the conditioned media of serum and
bFGF/heparin-treated cells. Northern blot analysis showed that PASMC
constitutively express TFPI mRNA, and treatment of cells with serum and
bFGF/heparin had a minimal effect on the steady-state levels of TFPI
mRNA. Nuclear run-on analysis did not show a significant increase in the transcriptional rate of TFPI gene in PASMC treated with serum or
bFGF/heparin. Cycloheximide, but not actinomycin-D, treatment inhibited
the serum and bFGF/heparin-induced increase in TFPI activity in PASMC.
In conclusion, our data demonstrate that PASMC constitutively
synthesize and secrete TFPI and serum or bFGF upregulate its
expression, suggesting that growth factors that can stimulate the
vessel wall in vivo might locally regulate TFPI expression. Our study
also suggests that control of TFPI expression by serum or bFGF occurs
via translational rather than transcriptional regulation.
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