Surface thrombomodulin modulates thrombin receptor responses on
vascular smooth muscle cells.
Grinnell, Brian W., and David T. Berg.
Department of Cardiovascular Research, Lilly Research Laboratories,
Lilly Corporate Center, Indianapolis, Indiana 46285-0522
APStracts 2:0364H, 1995.
Vascular smooth muscle cells produce the proteolytically activated
thrombin receptor. Under certain conditions, they have been reported
to synthesize thrombomodulin (TM), another thrombin receptor known to
convert the specificity of thrombin from cleavage of
procoagulant/proinflammatory substrates to the cleavage of the
anticoagulant/anti-inflammatory factor protein C. In this study, we
examined the role of TM in modulating thrombin-mediated cellular
responses. Using a thrombin receptor positive, TM negative rabbit
intimal smooth muscle cell line (RIC), we isolated cells expressing
varying levels of functional surface TM following transfection with
an expression vector containing the cDNA for full length TM. The
parent RIC (TM negative) line responded to a-thrombin and to agonist
peptide (SFLL) with both mitogenic response and phosphoinositol
release. However, transfected cells producing high levels of TM,
equivalent to the level on rabbit aortic endothelial cells, responded
to SFLL but not to [alpha]-thrombin. Whereas a-thrombin, SFLL and the
combination of SFLL and thrombin resulted in a mitogenic response in
the TM negative RIC line, the response to the agonist peptide could
be blocked by thrombin in the TM-producing cell line. The degree to
which thrombin receptor activation was blocked directly correlated
with the level of TM on the cell surface and high levels of thrombin
could overcome the inhibitory effect. Our data demonstrate that the
co-expression of TM with thrombin receptor on vascular smooth muscle
cells can result in a modulation of cellular responses to thrombin,
which could control thrombin-induced proliferative events following
vessel injury or insult.
Received 28 April 1995; accepted in final form 8 August 1995.
APS Manuscript Number H404-5.
Article publication pending Am. J. Physiol. (Heart Circ. Physiology).
ISSN 1080-4757 Copyright 1995 The American Physiological Society.
Published in APStracts on 24 August 1995.