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Prepublished online as a Blood First Edition Paper on May 13, 2002; DOI 10.1182/blood-2002-01-0046.
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Blood, 1 September 2002, Vol. 100, No. 5, pp. 1689-1698
HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY
Prolonged fluid shear stress induces a distinct set of
endothelial cell genes, most specifically lung Krüppel-like
factor (KLF2)
Rob J. Dekker,
Simone van Soest,
Ruud D. Fontijn,
Sonia Salamanca,
Philip G. de
Groot,
Ed VanBavel,
Hans Pannekoek, and
Anton J. G. Horrevoets
From the Departments of Biochemistry and Medical
Physics, Academic Medical Center, University of Amsterdam, The
Netherlands; and the Department of Hematology, University Medical
Center, Utrecht, The Netherlands.
The endothelium expresses a large repertoire of genes under
apparent transcriptional control of biomechanical forces, many of which
are neither cell-type nor flow specific. We set out to identify genes
that are uniquely flow responsive in human vascular endothelial cells.
Transcriptional profiling using commercial DNA microarrays identified
12 of 18 000 genes that were modulated at least 5-fold after 24 hours
of steady laminar flow (25 dyne/cm2). After a 7-day
exposure to unidirectional pulsatile flow (19 ± 12 dyne/cm2), only 3 of 12 remained elevated at least 5-fold.
A custom microarray of ~300 vascular cell-related gene fragments was
constructed, and expression analysis revealed that many flow-induced
genes are also induced by at least one of the following agents: tumor necrosis factor- (TNF-), interleukin-1 (IL-1),
transforming growth factor-, vascular endothelial growth factor, or
thrombin, indicating a more general role in adaptive or stress
responses. Most flow-induced genes were also induced by TNF- but not
IL-1, suggesting the involvement of reactive oxygen species. A
limited panel of genes that are unique for flow-exposed cultures was
identified, including lung Krüppel-like factor
(LKLF/KLF2) and cytochrome P450 1B1 (CYP1B1).
In marked contrast, both these genes were substantially repressed
by TNF-. LKLF but not CYP1B1 mRNA was detected
exclusively in the vascular endothelium of healthy human aorta by in
situ hybridization and appeared to be flow regulated. To date LKLF is
the first endothelial transcription factor that is uniquely induced by
flow and might therefore be at the molecular basis of the physiological
healthy, flow-exposed state of the endothelial cell.
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