Endothelial-to-mesenchymal transition contributes to fibro-proliferative XXXX and is modulated by fluid shear stress.

@entity1 @entity455 @entity19 @entity1373 @entity37775 @entity2334 @entity6976 @entity731
AIMS: Neointimal @entity1373 is a common feature of fibro-proliferative @entity455 and characterizes initial stages of @entity731 . Neointimal lesions mainly comprise smooth muscle-like cells. The presence of these lesions is related to local differences in shear stress. Neointimal cells may arise through migration and proliferation of smooth muscle cells from the media. However, a role for the endothelium as a source of smooth muscle-like cells has largely been disregarded. Here, we investigated the role of endothelial-to-mesenchymal transition (EndMT) in neointimal @entity1373 and atherogenesis, and studied its modulation by shear stress. METHODS AND RESULTS: In @entity1 @entity731 plaques and porcine aortic tissues, myo-endothelial cells were identified, suggestive for EndMT. Flow disturbance by @entity2334 in @entity19 similarly showed the presence of myo-endothelial cells specifically in regions exposed to disturbed flow. While uniform laminar shear stress (LSS) was found to inhibit EndMT, endothelial cells exposed to disturbed flow underwent EndMT, in vitro and in vivo, and showed atherogenic differentiation. Gain- and loss-of-function studies using a constitutive active mutant of @entity37775 and short hairpins targeting @entity6976 established a pivotal role for @entity6976 signalling in the inhibition of EndMT. CONCLUSION: Together, these data suggest that EndMT contributes to neointimal @entity1373 and induces atherogenic differentiation of endothelial cells. Importantly, we uncovered that EndMT is modulated by shear stress in an @entity6976 -dependent manner. These findings provide new insights in the role of adverse endothelial plasticity in @entity455 and identify a novel atheroprotective mechanism of uniform LSS, namely inhibition of EndMT.
