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(Circulation Research. 2006;98:1264.)
© 2006 American Heart Association, Inc.

Molecular Medicine

Dexamethasone Downregulates Calcification-Inhibitor Molecules and Accelerates Osteogenic Differentiation of Vascular Pericytes

Implications for Vascular Calcification

John Paul Kirton, Fiona L. Wilkinson, Ann E. Canfield, M. Yvonne Alexander

From the Wellcome Trust Centre for Cell-Matrix Research and Division of Cardiovascular and Endocrine Sciences, Faculty of Medical and Human Sciences, University of Manchester, UK.

Correspondence to Dr M. Yvonne Alexander, Division of Cardiovascular and Endocrine Sciences, University of Manchester, Core Technology Facility (3rd Floor), 46 Grafton St, Manchester M13 9NT, United Kingdom. E-mail yvonne.alexander{at}manchester.ac.uk

Vascular calcification is present in many pathological conditions and is recognized as a strong predictor of future cardiovascular events. Current evidence suggests that it is a regulated process involving inducing and inhibitory molecules. Glucocorticoids have great clinical importance as antiinflammatory drugs and can act as potent inducers of osteogenic differentiation in vitro. The effect of glucocorticoids on vascular cells in vivo remains obscure. Pericytes are pluripotent cells that can differentiate into osteoblasts, and recent evidence suggests that they could participate in vascular calcification. We hypothesized that the synthetic glucocorticoid dexamethasone would enhance the rate of pericyte differentiation and mineralization in vitro with a concomitant suppression of calcification-inhibitory molecules. Three weeks of dexamethasone treatment induced a 2-fold increase in (1) alkaline phosphatase activity, (2) calcium deposition, and (3) the number of nodules formed in vitro; and a reduction in the expression of matrix Gla protein (MGP), osteopontin (OPN), and vascular calcification-associated factor (VCAF) mRNAs. The glucocorticoid receptor antagonist Org 34116 abolished dexamethasone-accelerated pericyte differentiation, nodule formation, and mineralization. Data obtained using Org 34116, the transcription inhibitor actinomycin D, and the protein synthesis inhibitor cyclohexamide suggest that MGP, OPN, and VCAF mRNA abundance are controlled at different and multiple levels by dexamethasone. This is the first report showing that dexamethasone enhances the osteogenic differentiation of pericytes and downregulates genes associated with inhibition of mineralization. Our study highlights the need for further investigation into the long-term consequences of prolonged glucocorticoid therapy on vascular calcification.

Key Words: pericytes • differentiation • calcification • gene regulation • glucocorticoid

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