© 2000 American Heart Association, Inc.
Integrative Physiology |
Apoptosis Regulates Human Vascular Calcification In Vitro
Evidence for Initiation of Vascular Calcification by Apoptotic Bodies
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.
Correspondence to D. Proudfoot, Department of Medicine, University of Cambridge, Addenbrooke’s Hospital, Level 6, ACCI Building, Hills Rd, Cambridge CB2 2QQ, UK. E-mail dp{at}mole.bio.cam.ac.uk
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
45Ca 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.
Key Words: calcification • vascular smooth muscle • apoptosis • apoptotic bodies
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