title: Endothelial-to-mesenchymal transition contributes to fibro-proliferative vascular disease and is modulated by fluid shear stress.
abstract: OBJECTIVE
  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.
  
  
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Hanzeplein 1 (EA11), Groningen NL-9713GZ, The Netherlands j.a.j.moonen@umcg.nl.
authors.forename: Jan-Renier A J
authors.initials: JR
authors.lastname: Moonen
authors.affiliation: Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Hanzeplein 1 (EA11), Groningen NL-9713GZ, The Netherlands.
authors.forename: Ee Soo
authors.initials: ES
authors.lastname: Lee
authors.affiliation: Department of Dermatology, Venerology and Allergology, University of Wuerzburg, Wuerzburg, Germany.
authors.forename: Marc
authors.initials: M
authors.lastname: Schmidt
authors.affiliation: Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Hanzeplein 1 (EA11), Groningen NL-9713GZ, The Netherlands.
authors.forename: Monika
authors.initials: M
authors.lastname: Maleszewska
authors.affiliation: Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Hanzeplein 1 (EA11), Groningen NL-9713GZ, The Netherlands.
authors.forename: Jasper A
authors.initials: JA
authors.lastname: Koerts
authors.affiliation: Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Hanzeplein 1 (EA11), Groningen NL-9713GZ, The Netherlands.
authors.forename: Linda A
authors.initials: LA
authors.lastname: Brouwer
authors.affiliation: Department of Biomedical Engineering, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Theo G
authors.initials: TG
authors.lastname: van Kooten
authors.affiliation: Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Hanzeplein 1 (EA11), Groningen NL-9713GZ, The Netherlands.
authors.forename: Marja J A
authors.initials: MJ
authors.lastname: van Luyn
authors.affiliation: Department of Surgery, Division Vascular Surgery, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Clark J
authors.initials: CJ
authors.lastname: Zeebregts
authors.affiliation: Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Hanzeplein 1 (EA11), Groningen NL-9713GZ, The Netherlands.
authors.forename: Guido
authors.initials: G
authors.lastname: Krenning
authors.affiliation: Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Hanzeplein 1 (EA11), Groningen NL-9713GZ, The Netherlands.
authors.forename: Martin C
authors.initials: MC
authors.lastname: Harmsen
mesh_terms: D000818:Animals; D001013:Aorta, Thoracic / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D001018:Aortic Diseases / Q000235:genetics / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D002339:Carotid Arteries / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D002340:Carotid Artery Diseases / Q000235:genetics / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D049109:Cell Proliferation; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000378:metabolism / Q000473:pathology*; D058750:Epithelial-Mesenchymal Transition; D005355:Fibrosis; D057809:HEK293 Cells; D061307:Human Umbilical Vein Endothelial Cells / Q000378:metabolism / Q000473:pathology; D006801:Humans; D048671:MAP Kinase Kinase 5 / Q000235:genetics / Q000378:metabolism; D008297:Male; D040542:Mechanotransduction, Cellular; D008810:Mice, Inbred C57BL; D048054:Mitogen-Activated Protein Kinase 7 / Q000235:genetics / Q000378:metabolism; D058426:Neointima; D058226:Plaque, Atherosclerotic; D034622:RNA Interference; D012039:Regional Blood Flow; D013314:Stress, Mechanical; D013552:Swine; D013997:Time Factors; D014162:Transfection; D066253:Vascular Remodeling
chemical_list: C481581:MAPK7 protein, human; D048054:Mitogen-Activated Protein Kinase 7; D048671:MAP Kinase Kinase 5; C482565:Map2k5 protein, rat
keywords: ERK5; Endothelial-to-mesenchymal transition; Fibrosis; Neointimal hyperplasia; Shear stress