Abstract
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 TGFβ2 (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 TGFβ2 and inflammatory cytokines (interleukin 1β 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 TGFβ2 and inflammatory cytokines, then regions of the aorta under low versus high FSS were examined. TGFβ2 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.