Vascular endothelial cells respond to spatial gradients in fluid shear stress by enhanced activation of transcription factors

The vascular endothelium is exposed to a spectrum of fluid mechanical force s generated by blood flow; some of these, such as fluid shear stress, can d irectly modulate endothelial gene expression. previous work by others and i n our laboratory, using an in vitro uniform laminar shear stress models has identified various shear stress response elements (SSREs) within the promo ters of certain endothelial genes that: regulate their expression by intera cting with various transcription factors, including nuclear factor-kappa B (NF-KB), early growth response-1 (Egr-1), and activator protein-1 (AP-1, co mposed of c-Jun/c-Jun and c-Jun/c-Fos protein dimers). In the current study , we have examined the topographical patterns of NF-KB, Egr-1, c-Jun, and c -Fos activation in a specially designed in vitro disturbed laminar shear st ress model, which incorporates regions of significant spatial shear stress gradients similar to those found in atherosclerosis-prone arterial geometri es in vivo leg, arterial bifurcations, curvatures, ostial openings. Using n ewly developed quantitative image analysis techniques, we demonstrate that endothelial cells subjected to disturbed laminar shear stress exhibit incre ased levels of nuclear localized NF-KB, Egr-1, c-Jun, and c-Fos, compared w ith cells exposed to uniform laminar shear stress or maintained under stati c conditions. In addition, individual cells display a heterogeneity in resp onsiveness to disturbed flow, as measured by the amount of NF-KB, Egr-1, c- Jun, and c-Fos in their nuclei. This differential regulation of transcripti on factor expression by disturbed versus uniform laminar shear stress indic ates that regional differences in blood flow patterns in vivo-in particular , the occurrence of spatial shear stress gradients-may represent important local modulators of endothelial gene expression at anatomic sites predispos ed for atherosclerotic development.