© 1999 American Heart Association, Inc.
Vascular Biology |
Vascular Endothelial Cells Respond to Spatial Gradients in Fluid Shear Stress by Enhanced Activation of Transcription Factors
From the Vascular Research Division (M.A.G.), Departments of Pathology, Brigham and Women's Hospital, and Harvard Medical School, Boston, Mass; the Fluid Mechanics Laboratory (C.F.D.), Massachusetts Institute of Technology, and the Harvard-Massachusetts Institute of Technology Division of Health Sciences and Technology (T.N.), Cambridge, Mass; and the Department of Cell Biology (N.R.), Bruce Rappaport Research Institute, Technion Medical School, Haifa, Israel.
Correspondence to Michael A. Gimbrone, Jr, MD, Vascular Research Division, Department of Pathology, Brigham and Women's Hospital, 221 Longwood Avenue, LMRC-4, Boston, MA 02115. E-mail gimbrone{at}bustoff.bwh.harvard.edu
Abstract—The vascular
endothelium is exposed to a spectrum of fluid
mechanical forces generated by blood flow; some of these, such as fluid
shear stress, can directly modulate endothelial gene
expression. Previous work by others and in our laboratory, using an in
vitro uniform laminar shear stress model, has identified various shear
stress response elements (SSREs) within the promoters of certain
endothelial genes that regulate their expression by
interacting with various transcription factors, including nuclear
factor-
B (NF-B), early growth response-1 (Egr-1), and
activator protein-1 (AP-1, composed of c-Jun/c-Jun and
c-Jun/c-Fos protein dimers). In the current study, we have examined the
topographical patterns of NF-B, Egr-1, c-Jun, and c-Fos activation
in a specially designed in vitro disturbed laminar shear stress model,
which incorporates regions of significant spatial shear stress
gradients similar to those found in
atherosclerosis-prone arterial geometries
in vivo (eg, arterial bifurcations, curvatures, ostial
openings). Using newly developed quantitative image analysis
techniques, we demonstrate that endothelial cells
subjected to disturbed laminar shear stress exhibit increased levels of
nuclear localized NF-B, Egr-1, c-Jun, and c-Fos, compared with cells
exposed to uniform laminar shear stress or maintained under static
conditions. In addition, individual cells display a
heterogeneity in responsiveness to disturbed flow, as
measured by the amount of NF-B, Egr-1, c-Jun, and c-Fos in their
nuclei. This differential regulation of transcription factor expression
by disturbed versus uniform laminar shear stress indicates that
regional differences in blood flow patterns in vivo–in particular, the
occurrence of spatial shear stress gradients–may represent
important local modulators of endothelial gene
expression at anatomic sites predisposed for atherosclerotic
development.
Key Words: disturbed flow • nuclear factor-B • early growth response-1 • c-Jun • c-Fos
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