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Temporal gradients in shear, but not spatial gradients, stimulate ERK1/2 activation in human endothelial cells

¹La Jolla Bioengineering Institute, La Jolla; ²Center for Perinatal Biology, Loma Linda University, Loma Linda; and ³University of California, San Diego, La Jolla, California

Submitted 6 December 2004 ; accepted in final form 9 July 2005

We have previously demonstrated temporal gradients in shear stress stimulate endothelial cell proliferation, whereas spatial gradients do not. In the present study, the extracellular signal-regulated kinases 1 and 2 (ERK1/2) pathway was investigated as a possible mediator for the promitogenic effect of temporal gradients. The sudden expansion flow chamber (SEFC) model was used to differentiate the effect of temporal gradients in shear from that of spatial gradients on ERK1/2 activation in human umbilical vein endothelial cells (HUVEC). ERK1/2 activation in the SEFC was not significantly different from control when HUVEC were exposed to spatial gradients alone. When a single temporal impulse was superimposed on spatial gradients, ERK1/2 activation was stimulated 330% (relative to spatial alone) within the region of spatial gradients. Inhibition of the ERK1/2 pathway with U-0126 abolished all effects of temporal gradients. To further separate temporal and spatial gradients, a conventional parallel plate flow chamber was utilized. Acute exposure to oscillations in flow at a frequency of 1 Hz stimulated ERK1/2 activation 620 ± 88% relative to control, whereas a single impulse of flow increased ERK1/2 activation 166 ± 19%. Flow without the temporal component did not significantly activate ERK1/2. These results suggest that the ERK1/2 pathway directly mediates the promitogenic effects of temporal gradients in shear stress.

shear stress gradient; proliferation; recirculating flow; atherosclerosis