Chronic physiological shear stress inhibits tumor necrosis factor-induced proinflammatory responses in rabbit aorta perfused ex vivo.

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)-alpha-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-alpha-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-alpha (50 ng/mL, 6 hours) specifically stimulated vascular cell adhesion molecule (VCAM)-1 expression in ECs but not VSMCs. TNF-alpha-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-alpha-induced nuclear factor-kappaB activation. A nitric oxide synthesis inhibitor, NG-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.