© 1999 American Heart Association, Inc.
Original Contributions |
Temporal Gradient in Shear But Not Steady Shear Stress Induces PDGF-A and MCP-1 Expression in Endothelial Cells
Role of NO, NF
B, and egr-1
From the Department of Bioengineering, University of California, San Diego, La Jolla
Correspondence to Dr John A. Frangos, Department of Bioengineering, University of California, San Diego, 6407 Engineering Bldg Unit 1, 9500 Gilman Dr, La Jolla, CA 92093-0412. E-mail frangos{at}ucsd.edu
Abstract—Three well-defined
laminar flow profiles were created to distinguish the influence of a
gradient in shear and steady shear on platelet-derived growth
factor A (PDGF-A) and monocyte chemoattractant protein-1 (MCP-1)
expression in human endothelial cells. The flow
profiles (16 dyne/cm2 maximum shear stress) were ramp flow
(shear stress smoothly transited at flow onset), step flow (shear
stress abruptly applied at flow onset), and impulse flow (shear stress
abruptly applied for 3 s only). Ramp flow induced only minor
expression of PDGF-A and did not increase MCP-1 expression. Step flow
increased PDGF-A and MCP-1 mRNA levels 3- and 2-fold at 1.5 hours,
respectively, relative to ramp flow. In contrast, impulse flow
increased PDGF-A and MCP-1 expression 6- and 7-fold at 1.5 hours, and
these high levels were sustained for at least 4 hours. These results
indicate that a temporal gradient in shear (impulse flow and the onset
of step flow) and steady shear (ramp flow and the steady component of
step flow) stimulates and diminishes the expression of PDGF-A and
MCP-1, respectively. NO synthase inhibitor
NG-amino-L-arginine
(L-NAA) was found to markedly enhance MCP-1 and PDGF-A expression
induced by step flow, but decrease their expression induced by impulse
flow, in a dose-dependent manner. NO donor spermine-NONOate
(SPR/NO) dose-dependently reduced the MCP-1 and PDGF-A expression
induced by impulse flow. Moreover, impulse flow was found to stimulate
sustained (4 hours) I
B-
degradation and
egr-1 mRNA induction. L-NAA prevented IB-
degradation, whereas SPR/NO increased IB- resynthesis 2 hours
after impulse flow. Both L-NAA and SPR/NO inhibited the impulse flow
inducibility of egr-1 4 hours after the flow
stimulation. The results show that both NO induced by steady shear and
NO donor inhibit temporal gradient in shear-induced MCP-1 and PDGF-A
expression by downregulation of their respective transcription factors
NFB and egr-1, whereas NO induced by impulse flow
stimulates MCP-1 and PDGF-A expression by upregulation of the
transcription factors. The above findings suggest distinct roles of
temporal gradient in shear and steady shear in atherogenesis in
vivo.
Key Words: shear stress • gene expression • nitric oxide • transcription factor • atherosclerosis
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