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Chronic Mineral Dysregulation Promotes Vascular Smooth Muscle Cell Adaptation and Extracellular Matrix Calcification

Rukshana C. Shroff^*,,, Rosamund McNair, Jeremy N. Skepper^||, Nichola Figg, Leon J. Schurgers^¶, John Deanfield, Lesley Rees^* and Catherine M. Shanahan

*Nephrology and
Vascular Physiology Units, Great Ormond Street Hospital and University College London Institute of Child Health, London, United Kingdom;
British Heart Foundation Centre, Cardiovascular Division, King's College London, London, United Kingdom;
Department of Medicine, Addenbrooke's Hospital, Cambridge, United Kingdom;
^||Multi-Imaging Centre, Department of Anatomy, Cambridge, United Kingdom; and
^¶CArdiovascular Research Institute Maastricht and VitaK, University of Maastricht, Maastricht, Netherlands

Correspondence: Dr. Catherine Shanahan, BHF Centre, Cardiovascular Division, 125 Coldharbour Lane, King's College London, London SE5 9NU, UK. Phone: 44-20-7848-5221; Fax: 44-20-7848-5193; E-mail: cathy.shanahan{at}kcl.ac.uk

Received for publication June 29, 2009. Accepted for publication September 24, 2009.

In chronic kidney disease (CKD) vascular calcification occurs in response to deranged calcium and phosphate metabolism and is characterized by vascular smooth muscle cell (VSMC) damage and attrition. To gain mechanistic insights into how calcium and phosphate mediate calcification, we used an ex vivo model of human vessel culture. Vessel rings from healthy control subjects did not accumulate calcium with long-term exposure to elevated calcium and/or phosphate. In contrast, vessel rings from patients with CKD accumulated calcium; calcium induced calcification more potently than phosphate (at equivalent calcium-phosphate product). Elevated phosphate increased alkaline phosphatase activity in CKD vessels, but inhibition of alkaline phosphatase with levamisole did not block calcification. Instead, calcification in CKD vessels most strongly associated with VSMC death resulting from calcium- and phosphate-induced apoptosis; treatment with a pan-caspase inhibitor ZVAD ameliorated calcification. Calcification in CKD vessels was also associated with increased deposition of VSMC-derived vesicles. Electron microscopy confirmed increased deposition of vesicles containing crystalline calcium and phosphate in the extracellular matrix of dialysis vessel rings. In contrast, vesicle deposition and calcification did not occur in normal vessel rings, but we observed extensive intracellular mitochondrial damage. Taken together, these data provide evidence that VSMCs undergo adaptive changes, including vesicle release, in response to dysregulated mineral metabolism. These adaptations may initially promote survival but ultimately culminate in VSMC apoptosis and overt calcification, especially with continued exposure to elevated calcium.

Copyright © 2009 by the American Society of Nephrology. Online ISSN: 1533-3450 Print ISSN: 1046-6673