Smooth muscle cell phenotypic transition associated with calcification: upregulation of Cbfa1 and downregulation of smooth muscle lineage markers

SA Steitz, MY Speer, G Curinga, HY Yang… - Circulation …, 2001 - Am Heart Assoc
SA Steitz, MY Speer, G Curinga, HY Yang, P Haynes, R Aebersold, T Schinke, G Karsenty
Circulation research, 2001Am Heart Assoc
Bovine aortic smooth muscle cell (BASMC) cultures undergo mineralization on addition of
the organic phosphate donor, β-glycerophosphate (βGP). Mineralization is characterized by
apatite deposition on collagen fibrils and the presence of matrix vesicles, as has been
described in calcified vascular lesions in vivo as well as in bone and teeth. In the present
study, we used this model to investigate the molecular mechanisms driving vascular
calcification. We found that BASMCs lost their lineage markers, SM22α and smooth muscle …
Bovine aortic smooth muscle cell (BASMC) cultures undergo mineralization on addition of the organic phosphate donor, β-glycerophosphate (βGP). Mineralization is characterized by apatite deposition on collagen fibrils and the presence of matrix vesicles, as has been described in calcified vascular lesions in vivo as well as in bone and teeth. In the present study, we used this model to investigate the molecular mechanisms driving vascular calcification. We found that BASMCs lost their lineage markers, SM22α and smooth muscle α-actin, within 10 days of being placed under calcifying conditions. Conversely, the cells gained an osteogenic phenotype as indicated by an increase in expression and DNA-binding activity of the transcription factor, core binding factor α1 (Cbfa1). Moreover, genes containing the Cbfa1 binding site, OSE2, including osteopontin, osteocalcin, and alkaline phosphatase were elevated. The relevance of these in vitro findings to vascular calcification in vivo was further studied in matrix GLA protein null (MGP−/−) mice whose arteries spontaneously calcify. We found that arterial calcification was associated with a similar loss in smooth muscle markers and a gain of osteopontin and Cbfa1 expression. These data demonstrate a novel association of vascular calcification with smooth muscle cell phenotypic transition, in which several osteogenic proteins including osteopontin, osteocalcin, and the bone determining factor Cbfa1 are gained. The findings suggest a positive role for SMCs in promoting vascular calcification.
Am Heart Assoc