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The reorientation responses of endothelial cells to cyclic strain and shear stress are very different-they align parallel to the fluid shear and perpendicular to the strain direction. In straight vessels these stimuli reinforce each other to cause axial alignment. Under other conditions, one or the other stimulus may become dominant. There are, however, few detailed studies of cellular responses to multiple stimuli. Therefore, we investigated the combined effects of applying these stimuli at "equipotent" levels in reinforcing and counteracting fashion. Pure uniaxial cyclic strain of 2% at 0.5 Hz, steady fluid shear stress at 80 dyne/cm2 and pulsatile fluid shear stress at 20 ± 10 dyne/cm2 at 0.5 Hz produced the same time course of cell reorientation and were thus deemed equipotent. When steady shear or pulsatile shear were applied in a reinforcing manner with cyclic strain, the response appeared to be synergistic. When applied in a counteracting fashion, however, the response was not significantly different from that in static controls. These results suggest that the magnitude and direction of cyclic strain and fluid shear are important determinants, both individually and collectively, of endothelial cell response.