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Genesis and growth of extracellular-vesicle-derived microcalcification in atherosclerotic plaques
Open accessAbstract
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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Cites
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Measuring the global burden of disease
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Mechanisms of Acute Coronary Syndromes and Their Implications for Therapy
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Self-citationMechanical memory and dosing influence stem cell fate
Yang, C., Tibbitt, M. W., Basta, L. P., & Anseth, K. S. (2014) · Nature Materials · doi:10.1038/nmat3889 · Cited by 1,167
Smooth Muscle Cell Phenotypic Transition Associated With Calcification
Steitz, S. A., Speer, M. Y., Curinga, G., Yang, H.-Y. L., Haynes, P. A., Aebersold, R. H., Schinke, T., Karsenty, G., & Giachelli, C. M. (2001) · Circulation Research · doi:10.1161/hh2401.101070 · Cited by 830
Aikawa, E. R., Nahrendorf, M., Figueiredo, J., Świrski, F. K., Shtatland, T., Köhler, R. H., Jaffer, F. A., Aikawa, M., & Weissleder, R. (2007) · Circulation · doi:10.1161/circulationaha.107.732867 · Cited by 694
Self-citationSpotty Calcification Typifies the Culprit Plaque in Patients With Acute Myocardial Infarction
Ehara, S., 小林, 芳., Yoshiyama, M., Shimada, K., Shimada, Y., Fukuda, D., Nakamura, Y., Yamashita, H., Yamagishi, H., Takeuchi, K., et al. (2004) · Circulation · doi:10.1161/01.cir.0000148131.41425.e9 · Cited by 690
Calcium Density of Coronary Artery Plaque and Risk of Incident Cardiovascular Events
Criqui, M. H., Denenberg, J. O., Ix, J. H., McClelland, R. L., Wassel, C. L., Rifkin, D. E., Carr, J. J., Budoff, M. J., & Allison, M. A. (2014) · JAMA · doi:10.1001/jama.2013.282535 · Cited by 642
Matrix vesicles and calcification
Anderson, H. C. (2003) · Current Rheumatology Reports · doi:10.1007/s11926-003-0071-z · Cited by 606
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Durham, A. L., Speer, M. Y., Scatena, M., Giachelli, C. M., & Shanahan, C. M. (2018) · Cardiovascular Research · doi:10.1093/cvr/cvy010 · Cited by 1,156
Vascular smooth muscle cells in atherosclerosis
Basatemur, G. L., Jørgensen, H. F., Clarke, M. C. H., Bennett, M. R., & Mallat, Z. (2019) · Nature Reviews Cardiology · doi:10.1038/s41569-019-0227-9 · Cited by 1,099
The Role of Inflammation in Cardiovascular Disease
Henein, M. Y., Vancheri, S., Longo, G., & Vancheri, F. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms232112906 · Cited by 802
Extracellular vesicles in coronary artery disease
Boulanger, C. M., Loyer, X., Rautou, P., & Amabile, N. (2017) · Nature Reviews Cardiology · doi:10.1038/nrcardio.2017.7 · Cited by 533
Inflammation and cardiovascular disease: From mechanisms to therapeutics
Alfaddagh, A., Martin, S. S., Leucker, T. M., Michos, E. D., Blaha, M. J., Lowenstein, C. J., Jones, S. R., & Toth, P. P. (2020) · American Journal of Preventive Cardiology · doi:10.1016/j.ajpc.2020.100130 · Cited by 473
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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