Vascular Smooth Muscle Cell Calcification Is Mediated by Regulated Exosome Secretion
Abstract
Rationale: Matrix vesicles (MVs), secreted by vascular smooth muscle cells (VSMCs), form the first nidus for mineralization and fetuin-A, a potent circulating inhibitor of calcification, is specifically loaded into MVs. However, the processes of fetuin-A intracellular trafficking and MV biogenesis are poorly understood. Objective: The objective of this study is to investigate the regulation, and role, of MV biogenesis in VSMC calcification. Methods and Results: Alexa488-labeled fetuin-A was internalized by human VSMCs, trafficked via the endosomal system, and exocytosed from multivesicular bodies via exosome release. VSMC-derived exosomes were enriched with the tetraspanins CD9, CD63, and CD81, and their release was regulated by sphingomyelin phosphodiesterase 3. Comparative proteomics showed that VSMC-derived exosomes were compositionally similar to exosomes from other cell sources but also shared components with osteoblast-derived MVs including calcium-binding and extracellular matrix proteins. Elevated extracellular calcium was found to induce sphingomyelin phosphodiesterase 3 expression and the secretion of calcifying exosomes from VSMCs in vitro, and chemical inhibition of sphingomyelin phosphodiesterase 3 prevented VSMC calcification. In vivo, multivesicular bodies containing exosomes were observed in vessels from chronic kidney disease patients on dialysis, and CD63 was found to colocalize with calcification. Importantly, factors such as tumor necrosis factor-α and platelet derived growth factor-BB were also found to increase exosome production, leading to increased calcification of VSMCs in response to calcifying conditions. Conclusions: This study identifies MVs as exosomes and shows that factors that can increase exosome release can promote vascular calcification in response to environmental calcium stress. Modulation of the exosome release pathway may be as a novel therapeutic target for prevention.
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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 [148]
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- Authors
- 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., Shroff, R., Yin, X., Muller, K., Skepper, J. N., Mayr, M., Reutelingsperger, C. P., Chester, A., Bertazzo, S., Schurgers, L. J., & Shanahan, C. M.
- Affiliations
- King's College London (GB)
- From the British Heart Foundation Centre of Excellence, Cardiovascular Division, King’s College London, The James Black Centre, London, United Kingdom (A.N.K., I.D., D.S., M.F., P.S., D.A.-H., X.Y., M.M., C.M.S.); Department of Biochemistry—Vascular Aspects, Faculty of Medicine, Health and Life Science, Maastricht University, Maastricht, The Netherlands (M.L.L.C., C.P.R., L.J.S.); Hatter Cardiovascular Institute, University College London, London, United Kingdom (Y.Z., S.M.D.); Department of Imaging...
- ORCID
- Venue
- Circulation Research
- Published
- 2015-04-10
- Volume
- 116
- Issue
- 8
- Pages
- 1312-1323
- ISSN
- 0009-7330 (ISSN-L)
- 1524-4571
- OpenAlex
- W2159616443
- Cited by
- 525
- References
- 43
- Citations by year
- 2026: 28 · 2025: 25 · 2024: 40 · 2023: 39 · 2022: 59 · 2021: 72 · 2020: 66 · 2019: 53 · 2018: 36 · 2017: 48 · 2016: 44 · 2015: 13 · 2014: 1
- FWCI
- 20.40
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Circulation Research (publishedVersion)
- PubMed (publishedVersion)
- Research Publications (Maastricht University) (publishedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Research Portal (King's College London) (submittedVersion)
- Research Publications (Maastricht University) (submittedVersion)
- Funders
- British Heart Foundation (RG/09/008/27923, FS/13/2/29892, RG/11/14/29056)
- Kidney Research UK (RP39/2013)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Extracellular vesicles in disease
- Health Sciences › Medicine › Nephrology › Parathyroid Disorders and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Dermatological and Skeletal Disorders
- Keywords
- vascular calcification, vascular smooth muscle cells, exosomes, matrix vesicles, fetuin-A, multivesicular bodies, exosome biogenesis, tetraspanins, CD63, extracellular calcium, chronic kidney disease, TNF-α, PDGF-BB, intracellular trafficking
- MeSH terms
- Adolescent, Adult, Calcium, Cells, Cultured, Exocytosis, Female, Humans, Male, Middle Aged, Muscle, Smooth, Vascular, Sphingomyelin Phosphodiesterase, Time Factors, Transfection, Case-Control Studies, Cytokines, Protein Transport, Secretory Vesicles, Myocytes, Smooth Muscle, RNA Interference, Intercellular Signaling Peptides and Proteins, Proteomics, Exosomes, Young Adult, Tetraspanins, alpha-2-HS-Glycoprotein, Vascular Calcification
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