Published Online
on September 8, 2003

A more recent version of this article appeared on September 30, 2003

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Submitted on December 20, 2002
Revised on June 3, 2003
Accepted on June 6, 2003

Chronic Physiological Shear Stress Inhibits Tumor Necrosis Factor-Induced Proinflammatory Responses in Rabbit Aorta Perfused Ex Vivo

Hideyuki Yamawaki DVM, PhD, Stephanie Lehoux PhD, and Bradford C. Berk MD, PhD^*

From the Center for Cardiovascular Research (H.Y., B.C.B.), University of Rochester, Rochester, NY, and INSERM U541 (S.L.), Paris, France.

^* To whom correspondence should be addressed. E-mail: bradford_berk{at}urmc.rochester.edu.

Background--Regions in the vasculature exposed to steady laminar flow have a lower likelihood for atherosclerosis than regions exposed to disturbed flow with low shear stress. We previously found that laminar flow of short duration inhibited tumor necrosis factor (TNF)--mediated proinflammatory signaling in cultured endothelial cells (ECs). However, mechanisms responsible for the atheroprotective effects of physiological shear stress remain undefined. Therefore, we examined the effects of chronic shear stress on TNF--induced inflammatory responses using an ex vivo perfusion organ culture system.

Methods and Results--Rabbit aortas were exposed to low or normal shear stress (0.4 or 12 dyne/cm²) at a constant pressure for 24 to 26 hours. EC and vascular smooth muscle cell (VSMC) proteins were selectively purified. After exposure to low shear stress, TNF- (50 ng/mL, 6 hours) specifically stimulated vascular cell adhesion molecule (VCAM)-1 expression in ECs but not VSMCs. TNF--stimulated VCAM expression was inhibited significantly by preexposure to normal shear stress. Normal shear stress inhibited TNF (15 minutes) activation of mitogen-activated protein (MAP) kinases (c-Jun NH₂-terminal kinase [JNK], p38, extracellular signal-regulated kinase [ERK]) in ECs. Specific pharmacological inhibitors of JNK and p38 but not ERK significantly inhibited TNF-induced VCAM expression. Normal shear stress prevented the association of TNF receptor (TNFR)-1 with TNFR-associated factor (TRAF)-2. There was no effect of low or normal shear stress on TNF--induced nuclear factor-B activation. A nitric oxide synthesis inhibitor, N^G-nitro-L-arginine methyl ester, did not reverse the inhibitory effects of shear stress on VCAM expression.

Conclusions--These results suggest that physiological shear stress is antiinflammatory by specifically inhibiting MAP kinase signaling and inhibiting TRAF-2 interaction with TNFR-1.

Key words: blood flow • endothelium • signal transduction • atherosclerosis

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