Human vascular smooth muscle cells undergo vesicle-mediated calcification in response to changes in extracellular calcium and phosphate concentrations: a potential mechanism for accelerated vascular calcification in ESRD.
Patients with ESRD have a high circulating calcium (Ca) x phosphate (P) product and develop extensive vascular calcification that may contribute to their high cardiovascular morbidity. However, the cellular mechanisms underlying vascular calcification in this context are poorly understood. In an in vitro model, elevated Ca or P induced human vascular smooth muscle cell (VSMC) calcification independently and synergistically, a process that was potently inhibited by serum. Calcification was initiated by release from living VSMC of membrane-bound matrix vesicles (MV) and also by apoptotic bodies from dying cells. Vesicles released by VSMC after prolonged exposure to Ca and P contained preformed basic calcium phosphate and calcified extensively. However, vesicles released in the presence of serum did not contain basic calcium phosphate, co-purified with the mineralization inhibitor fetuin-A and calcified minimally. Importantly, MV released under normal physiologic conditions did not calcify, and VSMC were also able to inhibit the spontaneous precipitation of Ca and P in solution. The potent mineralization inhibitor matrix Gla protein was found to be present in MV, and pretreatment of VSMC with warfarin markedly enhanced vesicle calcification. These data suggest that in the context of raised Ca and P, vascular calcification is a modifiable, cell-mediated process regulated by vesicle release. These vesicles contain mineralization inhibitors derived from VSMC and serum, and perturbation of the production or function of these inhibitors would lead to accelerated vascular calcification.
Reynolds
Joanne L
JL
Department of Medicine, Addenbrooke's Hospital, Cambridge, United Kingdom.
Joannides
Alexis J
AJ
Skepper
Jeremy N
JN
McNair
Rosamund
R
Schurgers
Leon J
LJ
Proudfoot
Diane
D
Jahnen-Dechent
Willi
W
Weissberg
Peter L
PL
Shanahan
Catherine M
CM
D000293:Adolescent; D000328:Adult; D000368:Aged; D001011:Aorta; D017209:Apoptosis; D001769:Blood; D002114:Calcinosis / Q000150:complications / Q000209:etiology* / Q000517:prevention & control; D002118:Calcium / Q000008:administration & dosage / Q000378:metabolism* / Q000494:pharmacology; D011232:Chemical Precipitation; D002648:Child; D002675:Child, Preschool; D004357:Drug Synergism; D045604:Extracellular Fluid / Q000378:metabolism*; D006801:Humans; D066298:In Vitro Techniques; D007676:Kidney Failure, Chronic / Q000150:complications; D008875:Middle Aged; D009131:Muscle, Smooth, Vascular / Q000378:metabolism*; D032389:Myocytes, Smooth Muscle / Q000378:metabolism*; D009994:Osmolar Concentration; D010710:Phosphates / Q000008:administration & dosage / Q000378:metabolism* / Q000494:pharmacology; D014652:Vascular Diseases / Q000150:complications / Q000209:etiology* / Q000517:prevention & control
D010710:Phosphates; D002118:Calcium