© 1997 American Heart Association, Inc.
Articles |
Tissue Factor Pathway Inhibitor in Endothelial Cells Colocalizes With Glycolipid Microdomains/Caveolae
Regulatory Mechanism(s) of the Anticoagulant Properties of the Endothelium
From the Thrombosis Research Institute, London, UK (C.L., C.A.G., A.D.W., M.F.S., V.V.K., F.L.), and the Gaubius TNO Institute of Vascular Research, Leiden, The Netherlands (J.J.E.).
Correspondence to Dr Cristina Lupu, Thrombosis Research Institute, Emmanuel Kaye Building, Manresa Road, Chelsea, London SW3 6 LR, United Kingdom. E-mail: clupu{at}ceasar.tri-london.ac.uk
Abstract Tissue factor pathway inhibitor (TFPI),
the main downregulator of the procoagulant activity of tissue
factor
factor VIIa complex, locates in human
endothelial cells (EC) in culture as well-defined
clusters uniformly distributed both on the cell surface and
intracellularly. We here demonstrate by
immunofluorescence that TFPI colocalizes in EC with
caveolin, urokinase-type plasminogen activator
receptor, and glycosphingolipids. The localization of TFPI in caveolae
in resting endothelium is proved by double immunogold
electron microscopy for TFPI and caveolin. After
ultracentrifugation of rat lung or EC
homogenates through density gradients of Nycodenz, TFPI was
highly enriched at densities of 1.05 to 1.08 g/mL, together with
caveolin and alkaline phosphatase. By ELISA, more than half of the
cellular TFPI was detected in Triton X-100-insoluble extracts of EC.
TFPI incorporates [1-3H]ethanolamine and is cleaved from
the cell surface by phosphatidylinositol–phospholipase C, indicating a
specific glycosylphosphatidylinositol-anchorage mechanism for TFPI in
the plasma membrane. Clustering of TFPI and its localization in
caveolae are dependent on the presence of cholesterol in
the membrane. Agonist-induced stimulation of EC caused marked changes
of distribution for both TFPI and caveolin at subcellular level, with
subsequent increase of the cell surface–associated
inhibitory activity toward tissue factorfactor VIIa. Our
findings suggest that, beside their function in transcytosis,
potocytosis, cell surface proteolysis, and regulation of signal
transduction, caveolae also play a direct role in the regulation of EC
anticoagulant properties.
Key Words: tissue factor pathway inhibitor • endothelial cells • glycolipid microdomains • caveolae
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