© 1997 American Heart Association, Inc.
Articles |
Thrombomodulin Expression in Bovine Brain Capillaries
Anticoagulant Function of the Blood-Brain Barrier, Regional Differences, and Regulatory Mechanisms
Correspondence to Berislav V. Zlokovic, MD, 2025 Zonal Ave, RMR 506, Los Angeles, Calif 90033. E-mail zlokovic{at}hsc.usc.edu
Abstract Thrombomodulin (TM), a key cofactor of the
TM-protein C pathway, is of major biologic significance for the
antithrombotic properties of endothelial cells. Yet,
there is uncertainty whether TM is expressed in brain and what
mechanisms govern brain endothelial anticoagulant
activity. In this study, bovine brain capillaries were used as an in
vitro model of the blood-brain barrier to determine factors involved in
the regulation of TM expression in cerebral vasculature. Quantitative
competitive-polymerase chain reaction assay revealed significant
regional differences in the amount of brain capillary TM mRNA, ie,
cortical > cerebellar > pontine, consistent with
the reverse transcription-polymerase chain reaction findings in which
the abundance of TM mRNA was analyzed relative to ß-actin
mRNA. Regional differences in TM mRNA brain capillary level correlated
well with differences in protein C activation. The TM mRNA and activity
were not detectable in brain parenchyma. Pathogenic mediators of
ischemic stroke, interleukin 1ß (10 U/mL), and tumor necrosis
factor 
(10 U/mL), produced a time-dependent decrease in brain
capillary TM mRNA (t1/2 of 2.1 and 3.9 hours, respectively)
and reduced endothelial TM activity. Incubation of
brain capillaries with retinoic acid (10 µmol/L) and dibutyryl
cAMP (3 mmol/L) resulted in a 4-fold increase in TM mRNA at 4 and
8 hours, respectively, followed by an increase in protein C activation.
We conclude that TM at the blood-brain barrier is likely to be an
important physiologic anticoagulant in brain microcirculation. Its
downregulation by cytokines may contribute to ischemic
brain damage and potentially could be counteracted by retinoic acid
and cAMP.
Key Words: thrombomodulin • blood-brain barrier • cytokines • retinoic acid • cAMP
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