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dc.contributor.authorChappell, Joel
dc.contributor.authorHarman, Jennifer L
dc.contributor.authorNarasimhan, Vagheesh M
dc.contributor.authorYu, Haixiang
dc.contributor.authorFoote, Kirsty
dc.contributor.authorSimons, Benjamin D
dc.contributor.authorBennett, Martin R
dc.contributor.authorJørgensen, Helle F
dc.date.accessioned2016-11-22T14:46:20Z
dc.date.available2016-11-22T14:46:20Z
dc.date.issued2016-12-09
dc.identifier.issn0009-7330
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/261271
dc.description.abstractRATIONALE: Vascular smooth muscle cell (VSMC) accumulation is a hallmark of atherosclerosis and vascular injury. However, fundamental aspects of proliferation and the phenotypic changes within individual VSMCs, which underlie vascular disease, remain unresolved. In particular, it is not known whether all VSMCs proliferate and display plasticity or whether individual cells can switch to multiple phenotypes. OBJECTIVE: To assess whether proliferation and plasticity in disease is a general characteristic of VSMCs or a feature of a subset of cells. METHODS AND RESULTS: Using multicolor lineage labeling, we demonstrate that VSMCs in injury-induced neointimal lesions and in atherosclerotic plaques are oligoclonal, derived from few expanding cells. Lineage tracing also revealed that the progeny of individual VSMCs contributes to both alpha smooth muscle actin (aSma)-positive fibrous cap and Mac3-expressing macrophage-like plaque core cells. Costaining for phenotypic markers further identified a double-positive aSma+ Mac3+ cell population, which is specific to VSMC-derived plaque cells. In contrast, VSMC-derived cells generating the neointima after vascular injury generally retained the expression of VSMC markers and the upregulation of Mac3 was less pronounced. Monochromatic regions in atherosclerotic plaques and injury-induced neointima did not contain VSMC-derived cells expressing a different fluorescent reporter protein, suggesting that proliferation-independent VSMC migration does not make a major contribution to VSMC accumulation in vascular disease. CONCLUSIONS: We demonstrate that extensive proliferation of a low proportion of highly plastic VSMCs results in the observed VSMC accumulation after injury and in atherosclerotic plaques. Therapeutic targeting of these hyperproliferating VSMCs might effectively reduce vascular disease without affecting vascular integrity.
dc.description.sponsorshipThis work was funded by the British Heart Foundation grants to HFJ (PG/12/86/29930, FS/15/38/31516). HFJ and MRB acknowledge support from the BHF Oxbridge Centre of Regenerative Medicine [RM/13/3/30159] and the BHF Cambridge Centre of Research Excellence [RE/13/6/30180]. BDS acknowledges the support of the Wellcome Trust [098357/Z/12/Z].
dc.languageEnglish
dc.language.isoen
dc.publisherOvid Technologies (Wolters Kluwer Health)
dc.rightsAttribution 4.0 International
dc.rightsAttribution 4.0 International
dc.rightsAttribution 4.0 International
dc.rightsAttribution 4.0 International
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
dc.subjectmulti-color lineage tracing
dc.subjectcarotid ligation
dc.subjectvascular smooth muscle
dc.subjectvascular surgery
dc.subjectatherosclerosis
dc.subjectcarotid occlusive disease
dc.subjectvascular disease
dc.titleExtensive Proliferation of a Subset of Differentiated, yet Plastic, Medial Vascular Smooth Muscle Cells Contributes to Neointimal Formation in Mouse Injury and Atherosclerosis Models.
dc.typeArticle
dc.description.versionThis is the final version of the article. It first appeared from the American Heart Association via https://doi.org/10.1161/CIRCRESAHA.116.309799
prism.endingPage1323
prism.publicationDate2016
prism.publicationNameCirc Res
prism.startingPage1313
prism.volume119
dc.identifier.doi10.17863/CAM.6444
dcterms.dateAccepted2016-09-27
rioxxterms.versionofrecord10.1161/CIRCRESAHA.116.309799
rioxxterms.versionVoR
rioxxterms.licenseref.urihttp://creativecommons.org/licenses/by/4.0/
rioxxterms.licenseref.startdate2016-09-28
dc.contributor.orcidSimons, Benjamin [0000-0002-3875-7071]
dc.contributor.orcidBennett, Martin [0000-0002-2565-1825]
dc.identifier.eissn1524-4571
rioxxterms.typeJournal Article/Review
pubs.funder-project-idWellcome Trust (098357/Z/12/Z)
pubs.funder-project-idBritish Heart Foundation (None)
pubs.funder-project-idWellcome Trust (100574/Z/12/Z)
pubs.funder-project-idBritish Heart Foundation (PG/16/11/32021)
pubs.funder-project-idBritish Heart Foundation (FS/15/38/31516)
pubs.funder-project-idBritish Heart Foundation (None)
pubs.funder-project-idBritish Heart Foundation (None)
pubs.funder-project-idBritish Heart Foundation (None)
cam.issuedOnline2016-09-28
cam.orpheus.successThu Jan 30 12:56:58 GMT 2020 - The item has an open VoR version.
rioxxterms.freetoread.startdate2100-01-01


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Attribution 4.0 International
Except where otherwise noted, this item's licence is described as Attribution 4.0 International