Unidirectional and oscillatory shear stress differentially modulate NOSIIIgene expression

Atherosclerotic plaques preferentially develop in regions exposed to a low mean shear stress and cyclic reversal of flow direction (oscillatory flow). This contrasts with plaque-free zones where endothelial cells are exposed to unidirectional flow. Previous works from our laboratory using a unique e xperimental flow system demonstrated the existence of a differential regula tion of endothelial nitric oxide synthase (NOS III) gene expression by unid irectional and oscillatory flow patterns, We further studied the possible m echanisms responsible for selective unresponsiveness of NOS III gene regula tion to oscillatory flow. The results obtained demonstrate that (i) inducti on of the activity of the 1600-base-pair NOS III gene promoter by unidirect ional and oscillatory shear stress is modulated by similar mechanisms that involve NF-kappa B activation, but do not involve Res-dependent MAP kinase activation, and (ii) the lack of induction of NOS III gene regulation by os cillatory shear stress can be attributed to the activation of a yet unident ified negative cia-acting element present in the NOS III gene. (C) 2000 Aca demic Press.