High Fluid Shear Stress Inhibits Cytokine-Driven Smad2/3 Activation in Vascular Endothelial Cells

Background Atherosclerosis occurs preferentially in regions of low and disturbed fluid shear stress (FSS) but is limited in regions of high laminar FSS as a result of inhibition of endothelial inflammatory pathways. Recent work has identified endothelial to mesenchymal transition (EndMT) driven by TGF beta 2 (transforming growth factor beta 2)-Smad2/3 (mothers against decapentaplegic) signaling as a critical component of atherogenesis. However, interactions between FSS and EndMT in this context have not been investigated. Methods and Results Endothelial cells were treated with TGF beta 2 and inflammatory cytokines (interleukin 1 beta and tumor necrosis factor alpha) with or without high FSS in a parallel plate flow chamber. Smad2/3 nuclear translocation and target gene expression, assayed by immunofluorescence and quantitative polymerase chain reaction, revealed that high FSS blocked the Smad2/3-EndMT pathway. In vivo, mice were injected with TGF beta 2 and inflammatory cytokines, then regions of the aorta under low versus high FSS were examined. TGF beta 2 and inflammatory cytokine treatment stimulated Smad2/3 nuclear translocation and target gene expression predominantly in regions of low FSS with little effect in regions of high FSS. Conclusions High FSS inhibits endothelial Smad2/3 activation and EndMT in response to inflammatory mediators, resulting in selective EndMT at athero-susceptible, low FSS regions of arteries.

Automated summary

High FSS inhibits endothelial Smad2/3 activation and EndMT in response to inflammatory mediators, resulting in selective EndMT at athero-susceptible, low FSS regions of arteries.