Abstract:
AIMS:Neointimal hyperplasia is a common feature of fibro-proliferative vascular disease and characterizes initial stages of atherosclerosis. 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 hyperplasia and atherogenesis, and studied its modulation by shear stress. METHODS AND RESULTS:In human atherosclerotic plaques and porcine aortic tissues, myo-endothelial cells were identified, suggestive for EndMT. Flow disturbance by thoracic-aortic constriction in mice 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 MEK5 and short hairpins targeting ERK5 established a pivotal role for ERK5 signalling in the inhibition of EndMT. CONCLUSION:Together, these data suggest that EndMT contributes to neointimal hyperplasia and induces atherogenic differentiation of endothelial cells. Importantly, we uncovered that EndMT is modulated by shear stress in an ERK5-dependent manner. These findings provide new insights in the role of adverse endothelial plasticity in vascular disease and identify a novel atheroprotective mechanism of uniform LSS, namely inhibition of EndMT.
journal_name
Cardiovasc Resjournal_title
Cardiovascular researchauthors
Moonen JR,Lee ES,Schmidt M,Maleszewska M,Koerts JA,Brouwer LA,van Kooten TG,van Luyn MJ,Zeebregts CJ,Krenning G,Harmsen MCdoi
10.1093/cvr/cvv175subject
Has Abstractpub_date
2015-12-01 00:00:00pages
377-86issue
3eissn
0008-6363issn
1755-3245pii
cvv175journal_volume
108pub_type
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doi:
更新日期:1995-04-01 00:00:00
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更新日期:1979-03-01 00:00:00
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更新日期:2004-10-01 00:00:00