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Genesis and growth of extracellular-vesicle-derived microcalcification in atherosclerotic plaques
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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.
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“In early fibro-atheromas, calcification is observed as large granules in the necrotic core and surrounding ECM, resulting from a number of interrelated processes, including macrophage and VSMC-derived calcifying micro-vesicles 147-149 , release of apoptotic bodies 150 or the activity of osteochondrogenic cells 151 .”
From Vascular smooth muscle cells in atherosclerosis (2019) · cites this paper as [149]
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Metadata
- Authors
- Hutcheson, J. D., Goettsch, C., Bertazzo, S., Maldonado, N., Ruiz, J. L., Goh, W., Yabusaki, K., Faits, T., Bouten, C., Franck, G., Quillard, T., Libby, P., Aikawa, M., Weinbaum, S., & Aikawa, E.
- Affiliations
- Brigham and Women's Hospital (US)
- Eindhoven University of Technology (NL)
- City College of New York (US)
- Corresponding author
- Aikawa, Elena
- ORCID
- Venue
- Nature Materials
- Published
- 2016-01-11
- Volume
- 15
- Issue
- 3
- Pages
- 335-343
- ISSN
- 1476-1122 (ISSN-L)
- 1476-4660
- PMC
- PMC4767675
- OpenAlex
- W2257022282
- Cited by
- 419
- References
- 52
- Citations by year
- 2026: 32 · 2025: 40 · 2024: 44 · 2023: 38 · 2022: 62 · 2021: 47 · 2020: 50 · 2019: 36 · 2018: 28 · 2017: 24 · 2016: 18
- FWCI
- 14.43
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Nature Materials (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- TU/e Research Portal (submittedVersion, other-oa)
- CUNY Academic Works (City University of New York) (submittedVersion)
- Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
- TU/e Research Portal (submittedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Funders
- Brigham and Women's Hospital
- Harvard University (UL1 TR001102)
- Harvard Catalyst (UL1-TR-001102, TR001102)
- Kowa Company
- Imperial College London
- National Institutes of Health (UL1TR001102)
- National Heart, Lung, and Blood Institute (R01 HL 80472, R01HL114805, R01HL080472, R01HL109506)
- National Center for Research Resources
- National Center for Advancing Translational Sciences (TR001102)
- Topics
- Physical Sciences › Materials Science › Biomaterials › Calcium Carbonate Crystallization and Inhibition
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Dermatological and Skeletal Disorders
- Life Sciences › Immunology and Microbiology › Immunology › Atherosclerosis and Cardiovascular Diseases
- Keywords
- extracellular vesicles, microcalcifications, atherosclerotic plaque, arterial calcification, calcification, fibrous cap, collagen gel, mineral formation, plaque stability, collagen content, calcification morphology
- MeSH terms
- Extracellular Vesicles, Animals, Apolipoproteins E, Calcium, Carotid Arteries, Collagen, Coronary Disease, Extracellular Matrix, Humans, Mice, Knockout, Atherosclerosis, Mice
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