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Type 1 plasminogen activator inhibitor synthesis of endothelial cells is
downregulated by smooth muscle cells
G Christ, D Seiffert, P Hufnagl, A Gessl, J Wojta and BR Binder
Laboratory for Clinical Experimental Physiology, University of Vienna,
Austria.
Plasminogen activator inhibitor type 1 (PAI-1), the physiologic inhibitor
of both tissue-type plasminogen activator (tPA) and urokinase- type
plasminogen activator (uPA), is a major biosynthetic product of endothelial
cells in vitro; endothelial cells in vivo, in contrast, do not appear to
produce significant amounts of PAI-1 as made evident by in
situ-hybridization studies in normal mice. This suggests that the high rate
of PAI-1 synthesis of endothelial cells in vitro might be a result of the
culture conditions. When human umbilical vein endothelial cells (HUVEC)
were grown on human amniotic membranes, resembling the natural growth
support instead of coated plastic, their morphology was changed from the
cobblestone-like appearance on plastic to an in vivo like flagstone
pattern. However, this morphological change had no significant effect on
the synthesis and secretion of PAI-1. When smooth muscle cell (SMC)
conditioned media (CM) were added to HUVEC cultures, PAI-1 antigen
secretion of HUVEC was reduced by 40% to 60% as measured by enzyme-linked
immunosorbent assay (ELISA). Immunoprecipitation experiments using
36S-methionine metabolically labeled HUVEC and Northern blot analysis of
HUVEC PAI-1 mRNA indicate that this reduction was attributable to decreased
PAI-1 synthesis and reduced steady-state levels of both the 3.2 kb and 2.2
kb form of PAI-1 mRNA. This effect was dose-dependent and observed under
serum-containing as well as serum- free conditions, in the absence or
presence of endothelial cell growth supplement (ECGS, 0 to 100
micrograms/mL) and attributable to a nondialyzable factor. Our data suggest
that the high level of PAI-1 biosynthesis of endothelial cells in vitro may
be attributable to the lack of a soluble factor produced by SMC, which
controls and suppresses PAI-1 biosynthesis of endothelial cells in vivo.
Volume 81,
Issue 5,
pp. 1277-1283,
03/01/1993
Copyright © 1993 by The American Society of Hematology
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