Evrard, Solene M.Lecce, LauraMichelis, Katherine C.Nomura-Kitabayashi, AyaPandey, GauravPurushothaman, K-Ramand'Escamard, ValentinaLi, Jennifer R.Hadri, LahouariaFujitani, KenjiMoreno, Pedro R.Benard, LudovicRimmele, PaulineCohain, AriellaMecham, BrighamRandolph, Gwendalyn J.Nabel, Elizabeth G.Hajjar, RogerFuster, ValentinBoehm, ManfredKovacic, Jason C.2017-10-302017-10-302016Nat Commun. 2016; 7:118532041-1723http://hdl.handle.net/20.500.12105/5226Endothelial to mesenchymal transition (EndMT) plays a major role during development, and also contributes to several adult cardiovascular diseases. Importantly, mesenchymal cells including fibroblasts are prominent in atherosclerosis, with key functions including regulation of: inflammation, matrix and collagen production, and plaque structural integrity. However, little is known about the origins of atherosclerosis-associated fibroblasts. Here we show using endothelial-specific lineage-tracking that EndMT-derived fibroblast-like cells are common in atherosclerotic lesions, with EndMT-derived cells expressing a range of fibroblast-specific markers. In vitro modelling confirms that EndMT is driven by TGF-beta signalling, oxidative stress and hypoxia; all hallmarks of atherosclerosis. `Transitioning' cells are readily detected in human plaques co-expressing endothelial and fibroblast/mesenchymal proteins, indicative of EndMT. The extent of EndMT correlates with an unstable plaque phenotype, which appears driven by altered collagen-MMP production in EndMT-derived cells. We conclude that EndMT contributes to atherosclerotic patho-biology and is associated with complex plaques that may be related to clinical events.engVoRhttp://creativecommons.org/licenses/by/4.0/FIBROBLAST ACTIVATION PROTEINAMERICAN-HEART-ASSOCIATIONMARROW-DERIVED CELLSSMOOTH-MUSCLE-CELLSIN-VIVOPULMONARY-HYPERTENSIONCARDIAC FIBROSISRENAL FIBROSISEXPRESSIONMICEAtribución 4.0 Internacional27340017710.1038/ncomms11853Nature Communicationsopen access