title: Genesis and growth of extracellular-vesicle-derived microcalcification in atherosclerotic plaques.
abstract: Clinical evidence links arterial calcification and cardiovascular risk. Finite-element modelling of the stress distribution within atherosclerotic plaques has suggested that subcellular microcalcifications in the fibrous cap may promote material failure of the plaque, but that large calcifications can stabilize it. Yet the physicochemical mechanisms underlying such mineral formation and growth in atheromata remain unknown. Here, by using three-dimensional collagen hydrogels that mimic structural features of the atherosclerotic fibrous cap, and high-resolution microscopic and spectroscopic analyses of both the hydrogels and of calcified human plaques, we demonstrate that calcific mineral formation and maturation results from a series of events involving the aggregation of calcifying extracellular vesicles, and the formation of microcalcifications and ultimately large calcification areas. We also show that calcification morphology and the plaque's collagen content-two determinants of atherosclerotic plaque stability-are interlinked.
authors.affiliation: Center for Interdisciplinary Cardiovascular Sciences, Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Joshua D
authors.initials: JD
authors.lastname: Hutcheson
authors.affiliation: Center for Interdisciplinary Cardiovascular Sciences, Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Claudia
authors.initials: C
authors.lastname: Goettsch
authors.affiliation: Department of Medical Physics &Biomedical Engineering, University College London, London WC1E 6BT, UK.
authors.forename: Sergio
authors.initials: S
authors.lastname: Bertazzo
authors.affiliation: Center for Interdisciplinary Cardiovascular Sciences, Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Natalia
authors.initials: N
authors.lastname: Maldonado
authors.affiliation: Center for Interdisciplinary Cardiovascular Sciences, Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Jessica L
authors.identifier: http://orcid.org/0000-0002-7986-0817
authors.initials: JL
authors.lastname: Ruiz
authors.affiliation: Center for Interdisciplinary Cardiovascular Sciences, Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Wilson
authors.initials: W
authors.lastname: Goh
authors.affiliation: Center for Interdisciplinary Cardiovascular Sciences, Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Katsumi
authors.initials: K
authors.lastname: Yabusaki
authors.affiliation: Center for Interdisciplinary Cardiovascular Sciences, Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Tyler
authors.initials: T
authors.lastname: Faits
authors.affiliation: Department of Biomedical Engineering &Institute for Complex Molecular Systems, Eindhoven University of Technology, 5600 MB Eindhoven, The Netherlands.
authors.forename: Carlijn
authors.initials: C
authors.lastname: Bouten
authors.affiliation: Center for Excellence in Vascular Biology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Gregory
authors.initials: G
authors.lastname: Franck
authors.affiliation: Center for Excellence in Vascular Biology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Thibaut
authors.initials: T
authors.lastname: Quillard
authors.affiliation: Center for Excellence in Vascular Biology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Peter
authors.initials: P
authors.lastname: Libby
authors.affiliation: Center for Interdisciplinary Cardiovascular Sciences, Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.|Center for Excellence in Vascular Biology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Masanori
authors.initials: M
authors.lastname: Aikawa
authors.affiliation: Department of Biomedical Engineering, City College of New York, New York, New York 10031, USA.
authors.forename: Sheldon
authors.initials: S
authors.lastname: Weinbaum
authors.affiliation: Center for Interdisciplinary Cardiovascular Sciences, Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.|Center for Excellence in Vascular Biology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Elena
authors.initials: E
authors.lastname: Aikawa
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics / Q000378:metabolism; D050197:Atherosclerosis / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism; D002339:Carotid Arteries / Q000473:pathology; D003094:Collagen / Q000378:metabolism; D003327:Coronary Disease / Q000378:metabolism; D005109:Extracellular Matrix; D000067128:Extracellular Vesicles / Q000502:physiology*; D006801:Humans; D051379:Mice; D018345:Mice, Knockout
chemical_list: D001057:Apolipoproteins E; D003094:Collagen; D002118:Calcium