Apoptosis Regulates Human Vascular Calcification In Vitro: Evidence for Initiation of Vascular Calcification by Apoptotic Bodies

Proudfoot, Diane; Skepper, Jeremy N.; Hegyi, Laszlo; Bennett, Martin R.; Shanahan, Catherine M.; Weissberg, Peter L.

doi:10.1161/01.res.87.11.1055

Cited by 719Dermatological and Skeletal DisordersParathyroid Disorders and TreatmentsAlkaline Phosphatase Research Studies

Apoptosis Regulates Human Vascular Calcification In Vitro: Evidence for Initiation of Vascular Calcification by Apoptotic Bodies

Proudfoot, Diane, Skepper, Jeremy N., Hegyi, Laszlo, Bennett, Martin R., Shanahan, Catherine M., Weissberg, Peter L.·2000·Circulation Research

DOI 10.1161/01.res.87.11.1055

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Abstract

Abstract —The mechanisms involved in the initiation of vascular calcification are not known, but matrix vesicles, the nucleation sites for calcium crystal formation in bone, are likely candidates, because similar structures have been found in calcified arteries. The regulation of matrix vesicle production is poorly understood but is thought to be associated with apoptotic cell death. In the present study, we investigated the role of apoptosis in vascular calcification. We report that apoptosis occurs in a human vascular calcification model in which postconfluent vascular smooth muscle cell (VSMC) cultures form nodules spontaneously and calcify after ≈28 days. Apoptosis occurred before the onset of calcification in VSMC nodules and was detected by several methods, including nuclear morphology, the TUNEL technique, and external display of phosphatidyl serine. Inhibition of apoptosis with the caspase inhibitor ZVAD.fmk reduced calcification in nodules by ≈40%, as measured by the cresolphthalein method and alizarin red staining. In addition, when apoptosis was stimulated in nodular cultures with anti-Fas IgM, there was a 10-fold increase in calcification. Furthermore, incubation of VSMC-derived apoptotic bodies with 45 Ca demonstrated that, like matrix vesicles, they can concentrate calcium. These observations provide evidence that apoptosis precedes VSMC calcification and that apoptotic bodies derived from VSMCs may act as nucleating structures for calcium crystal formation.

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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 [150]

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Authors: Proudfoot, D., Skepper, J. N., Hegyi, L., Bennett, M. R., Shanahan, C. M., & Weissberg, P. L.
Affiliations: University of Cambridge (GB)
From the Department of Medicine, University of Cambridge, Addenbrooke’s Hospital (D.P., L.H., M.R.B., C.M.H., P.L.W) and Department of Anatomy, Multi-Imaging Centre (J.N.S.), Cambridge, UK.
ORCID: Proudfoot, Diane
Skepper, Jeremy N.
Bennett, Martin R.
Shanahan, Catherine M.
Venue: Circulation Research
Publisher: Ovid Technologies (Wolters Kluwer Health)
Published: 2000-11-24
Volume: 87
Issue: 11
Pages: 1055-1062
ISSN: 0009-7330 (ISSN-L)
1524-4571
DOI: 10.1161/01.res.87.11.1055
OpenAlex: W2124591820
Cited by: 719
References: 38
Citations by year: 2026: 21 · 2025: 20 · 2024: 38 · 2023: 25 · 2022: 47 · 2021: 44 · 2020: 51 · 2019: 34 · 2018: 39 · 2017: 37 · 2016: 30 · 2015: 32 · 2014: 44 · 2013: 39 · 2012: 32
FWCI: 5.05
Type: journal article
Language: en
Open access: closed
Locations: Circulation Research (publishedVersion)
PubMed (publishedVersion)
Funders: Wellcome Trust
British Heart Foundation
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Dermatological and Skeletal Disorders
Health Sciences › Medicine › Nephrology › Parathyroid Disorders and Treatments
Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Alkaline Phosphatase Research Studies
Keywords: vascular calcification, apoptosis, vascular smooth muscle cells, matrix vesicles, apoptotic bodies, caspase inhibition, Fas, phosphatidylserine
MeSH terms: Amino Acid Chloromethyl Ketones, Anthraquinones, Calcinosis, Calcium, Calcium Radioisotopes, Cell Division, Cells, Cultured, Cycloheximide, Coloring Agents, Electron Probe Microanalysis, Humans, Immunoglobulin M, Muscle, Smooth, Vascular, Protein Synthesis Inhibitors, Apoptosis, fas Receptor, Ki-67 Antigen, In Situ Nick-End Labeling

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Apoptosis Regulates Human Vascular Calcification In Vitro: Evidence for Initiation of Vascular Calcification by Apoptotic Bodies

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