Macrophage-Derived Matrix Vesicles: An Alternative Novel Mechanism for Microcalcification in Atherosclerotic Plaques
Open accessAbstract
Rationale: We previously showed that early calcification of atherosclerotic plaques associates with macrophage accumulation. Chronic renal disease and mineral imbalance accelerate calcification and the subsequent release of matrix vesicles (MVs), precursors of microcalcification. Objective: We tested the hypothesis that macrophage-derived MVs contribute directly to microcalcification. Methods and Results: Macrophages associated with regions of calcified vesicular structures in human carotid plaques (n=136 patients). In vitro, macrophages released MVs with high calcification and aggregation potential. MVs expressed exosomal markers (CD9 and TSG101) and contained S100A9 and annexin V. Silencing S100A9 in vitro and genetic deficiency in S100A9 −/− mice reduced MV calcification, whereas stimulation with S100A9 increased calcification potential. Externalization of phosphatidylserine after Ca/P stimulation and interaction of S100A9 and annexin V indicated that a phosphatidylserine-annexin V-S100A9 membrane complex facilitates hydroxyapatite nucleation within the macrophage-derived MV membrane. Conclusions: Our results support the novel concept that macrophages release calcifying MVs enriched in S100A9 and annexin V, which contribute to accelerated microcalcification in chronic renal disease.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In early fibroatheromas, calcification is observed as large granules in the necrotic core and surrounding ECM, resulting from interrelated processes including macrophage and VSMC-derived calcifying micro-vesicles, release of apoptotic bodies, or activity of osteochondrogenic cells.
“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 [147]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
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 · see citing works
Self-citationMatrix vesicles and calcification
Anderson, H. C. (2003) · Current Rheumatology Reports · doi:10.1007/s11926-003-0071-z · Cited by 606 · see citing works
Stabilization of atherosclerotic plaques: New mechanisms and clinical targets
Libby, P., & Aikawa, M. (2002) · Nature Medicine · doi:10.1038/nm1102-1257 · Cited by 581 · see citing works
Self-citationVascular calcification in chronic kidney disease
Goodman, W. G., London, G. M., Amann, K., Block, G. A., Giachelli, C. M., Hruska, K. A., Ketteler, M., Levin, A., Massy, Z. A., McCarron, D. A., et al. (2004) · American Journal of Kidney Diseases · doi:10.1053/j.ajkd.2003.12.005 · Cited by 417 · see citing works
Self-citationKapustin, A. N., Davies, J. D., Reynolds, J. L., McNair, R., Jones, G. T., Sidibe, A., Schurgers, L. J., Skepper, J. N., Proudfoot, D., Mayr, M., et al. (2011) · Circulation Research · doi:10.1161/circresaha.110.238808 · Cited by 417 · see citing works
Self-citationMolecular Imaging Insights Into Early Inflammatory Stages of Arterial and Aortic Valve Calcification
New, S. E. P., & Aikawa, E. R. (2011) · Circulation Research · doi:10.1161/circresaha.110.234146 · Cited by 347 · see citing works
Self-citationAikawa, E. R., Aikawa, M., Libby, P., Figueiredo, J., Rusanescu, G., Iwamoto, Y., Fukuda, D., Köhler, R. H., Shi, G., Jaffer, F. A., et al. (2009) · Circulation · doi:10.1161/circulationaha.108.827972 · Cited by 309 · see citing works
Self-citationCalcification of matrix vesicles in human aortic valve and aortic media.
Km, K. (1976) · PubMed · Cited by 260 · see citing works
Myeloid-Related Protein-8/14 Is Critical for the Biological Response to Vascular Injury
Croce, K., Gao, H., Wang, Y., Mooroka, T., Sakuma, M., Shi, C., Sukhova, G. K., Packard, R. R. S., Hogg, N., Libby, P., et al. (2009) · Circulation · doi:10.1161/circulationaha.108.814582 · Cited by 254 · see citing works
Self-citationS100A8 and S100A9 in Human Arterial Wall
McCormick, M. M., Rahimi, F., Bobryshev, Y. V., Gaus, K., Zreiqat, H., Cai, H., Lord, R. S. A., & Geczy, C. L. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.m509442200 · Cited by 186 · see citing works
Annexin-Mediated Matrix Vesicle Calcification in Vascular Smooth Muscle Cells
Chen, N. X., O’Neill, K. D., Chen, X., et al. (2008) · Journal of Bone and Mineral Research · doi:10.1359/jbmr.080604 · Cited by 170 · see citing works
Functional Differences Between Growth Plate Apoptotic Bodies and Matrix Vesicles
Kirsch, T., Wang, W., & Pfander, D. (2003) · Journal of Bone and Mineral Research · doi:10.1359/jbmr.2003.18.10.1872 · Cited by 86 · see citing works
Grskovic, I., Kutsch, A., Frie, C., et al. (2012) · Journal of Bone and Mineral Research · doi:10.1002/jbmr.1682 · Cited by 48 · see citing works
Wenk, J. F., Papadopoulos, P., & Zohdi, T. I. (2010) · Journal of Biomechanical Engineering · doi:10.1115/1.4001351 · Cited by 43 · see citing works
Bode, G., Lueken, A., Kerkhoff, C., et al. (2008) · Journal of Biological Chemistry · doi:10.1074/jbc.m803908200 · Cited by 41 · see citing works
Li, R., Mittelstein, D. R., Lee, J., Fang, K., Majumdar, R., Tintut, Y., Demer, L. L., & Hsiai, T. K. (2011) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.00313.2011 · Cited by 25 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Lindman, B. R., Clavel, M.-A., Mathieu, P., Iung, B., Lancellotti, P., Otto, C. M., & Pibarot, P. (2016) · Nature Reviews Disease Primers · doi:10.1038/nrdp.2016.6 · Cited by 982 · see citing works
Vascular Smooth Muscle Cell Calcification Is Mediated by Regulated Exosome Secretion
Kapustin, A. N., Chatrou, M. L. L., Drozdov, I., Zheng, Y., Davidson, S. M., Soong, D., Furmanik, M., Sanchis, P., De Rosales, R. T. M., Alvarez-Hernandez, D., et al. (2015) · Circulation Research · doi:10.1161/circresaha.116.305012 · Cited by 525 · see citing works
Self-citationGenesis and growth of extracellular-vesicle-derived microcalcification in atherosclerotic plaques
Hutcheson, J. D., Goettsch, C., Bertazzo, S., Maldonado, N., Ruiz, J. L., Goh, W., Yabusaki, K., Faits, T., Bouten, C., Franck, G., et al. (2016) · Nature Materials · doi:10.1038/nmat4519 · Cited by 419 · see citing works
Self-citationBlaser, M. C., Buffolo, F., Halu, A., Turner, M. E., Schlotter, F., Higashi, H., Pantano, L., Clift, C. L., Saddic, L. A., Atkins, S. K., et al. (2023) · Circulation · doi:10.1161/circulationaha.122.063402 · Cited by 114 · see citing works
Self-citationLi, Z., Zhao, Z., Cai, Z., Sun, Y., Li, L., Yao, F., Yang, L., Zhou, Y., Zhu, H., Fu, Y., et al. (2020) · Arteriosclerosis, Thrombosis, and Vascular Biology · doi:10.1161/atvbaha.119.314113 · Cited by 46 · see citing works
Advancements in the application of deep learning for coronary artery calcification
Tang, K.-X., Wu, Y.-L., Shan, S.-K., & Yuan, L.-Q. (2025) · Meta-Radiology · doi:10.1016/j.metrad.2025.100134 · Cited by 2 · see citing works
- Authors
- New, S. E. P., Goettsch, C., Aikawa, M., Marchini, J. F., Shibasaki, M., Yabusaki, K., Libby, P., Shanahan, C. M., Croce, K., & Aikawa, E.
- Affiliations
- Brigham and Women's Hospital (US)
- From the Center for Interdisciplinary Cardiovascular Sciences (S.E.P.N., C.G., M.A., M.S., K.Y., E.A.) and Cardiovascular Division and Center for Excellence in Vascular Biology, Cardiovascular Medicine (M.A., J.F.M., P.L., E.A.), Brigham and Women’s Hospital, Harvard Medical School, Boston, MA; and Cardiovascular Division, King’s College, London, United Kingdom (C.M.S.).
- ORCID
- Venue
- Circulation Research
- Published
- 2013-06-21
- Volume
- 113
- Issue
- 1
- Pages
- 72-77
- ISSN
- 0009-7330 (ISSN-L)
- 1524-4571
- PMC
- PMC3703850
- OpenAlex
- W4251327626
- Cited by
- 451
- References
- 16
- Citations by year
- 2026: 19 · 2025: 28 · 2024: 38 · 2023: 32 · 2022: 47 · 2021: 45 · 2020: 51 · 2019: 36 · 2018: 28 · 2017: 33 · 2016: 43 · 2015: 21 · 2014: 24 · 2013: 6
- FWCI
- 23.75
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Circulation Research (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Research Portal (King's College London) (submittedVersion)
- Funders
- Brigham and Women's Hospital
- Kowa Company
- British Heart Foundation (RG/11/14/29056)
- National Institutes of Health
- National Heart, Lung, and Blood Institute (K08HL086672, R01 HL 80472, R01HL114805, R01HL080472)
- Topics
- Health Sciences › Medicine › Nephrology › Parathyroid Disorders and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Extracellular vesicles in disease
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › S100 Proteins and Annexins
- Keywords
- microcalcifications, atherosclerotic plaque calcification, S100A9, annexin V, phosphatidylserine, hydroxyapatite nucleation, chronic kidney disease, carotid plaque, exosomes, macrophage aggregation, mineral imbalance
- MeSH terms
- Animals, Apolipoproteins E, Calcinosis, Calcium, Carotid Artery Diseases, Cell Line, Humans, Macrophages, Membrane Lipids, Membrane Proteins, Mice, Inbred C57BL, Phosphatidylserines, Phosphorus, Annexin A5, Macrophages, Peritoneal, Durapatite, Mice, Knockout, Cytoplasmic Vesicles, RNA Interference, RNA, Small Interfering, Calgranulin B, Mice, Plaque, Atherosclerotic
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
