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Publication
Endothelial-to-mesenchymal transition drives atherosclerosis progression.
Authors Chen PY, Qin L, Baeyens N, Li G, Afolabi T, Budatha M, Tellides G, Schwartz MA,
Simons M
Submitted By Submitted Externally on 8/16/2017
Status Published
Journal The Journal of clinical investigation
Year 2015
Date Published 10/26/2015
Volume : Pages 125 : 4514 - 28
PubMed Reference 26517696
Abstract The molecular mechanisms responsible for the development and progression of
atherosclerotic lesions have not been fully established. Here, we investigated
the role played by endothelial-to-mesenchymal transition (EndMT) and its key
regulator FGF receptor 1 (FGFR1) in atherosclerosis. In cultured human
endothelial cells, both inflammatory cytokines and oscillatory shear stress
reduced endothelial FGFR1 expression and activated TGF-ß signaling. We further
explored the link between disrupted FGF endothelial signaling and progression of
atherosclerosis by introducing endothelial-specific deletion of FGF receptor
substrate 2 a (Frs2a) in atherosclerotic (Apoe(-/-)) mice. When placed on a
high-fat diet, these double-knockout mice developed atherosclerosis at a much
earlier time point compared with that their Apoe(-/-) counterparts, eventually
demonstrating an 84% increase in total plaque burden. Moreover, these animals
exhibited extensive development of EndMT, deposition of fibronectin, and
increased neointima formation. Additionally, we conducted a molecular and
morphometric examination of left main coronary arteries from 43 patients with
various levels of coronary disease to assess the clinical relevance of these
findings. The extent of coronary atherosclerosis in this patient set strongly
correlated with loss of endothelial FGFR1 expression, activation of endothelial
TGF-ß signaling, and the extent of EndMT. These data demonstrate a link between
loss of protective endothelial FGFR signaling, development of EndMT, and
progression of atherosclerosis.




Strains
StrainDevelopment StatusCreation MethodOptions
B6.129P2-Apoetm1Unc/JPhenotyping ongoingknockout
View
B6.129S7-Frs2tm1FwanPhenotyping ongoingknockin
View




Genes
SymbolDescription
Apoeapolipoprotein E
Frs2fibroblast growth factor receptor substrate 2

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