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Nat Commun. 2016 Jun 24;7:11853. doi: 10.1038/ncomms11853.

Endothelial to mesenchymal transition is common in atherosclerotic lesions and is associated with plaque instability.

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The Zena and Michael A. Wiener Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.
Department of Genetics and Genomic Sciences and Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.
Trialomics LLC, Seattle, Washington 98115, USA.
Department of Pathology and Immunology, Washington University, St Louis, Missouri 63110, USA.
Brigham and Women's Health Care, Boston, Massachusetts 02115, USA.
Marie-Josée and Henry R. Kravis Cardiovascular Health Center, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.
Centro Nacional de Investigaciones Cardiovasculares (CNIC), 28029 Madrid, Spain.
Center for Molecular Medicine, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland, 20892, USA.


Endothelial 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-β 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.

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