Medial localization of mineralization-regulating proteins in association with Monckeberg's sclerosis - Evidence for smooth muscle cell-mediated vascular calcification

Background-Calcification of the media of peripheral arteries is referred to as Monckeberg's sclerosis (MS) and occurs commonly in aged and diabetic in dividuals. Its pathogenesis is unknown, but its presence predicts risk of c ardiovascular events and leg amputation in diabetic patients. Several studi es have documented expression of bone-associated genes in association with intimal atherosclerotic calcification, leading to the suggestion that vascu lar calcification may be a regulated process with similarities to developme ntal osteogenesis. Therefore, we examined gene expression in vessels with M S to determine whether there was evidence for a regulated calcification pro cess in the vessel media. Methods and Results-In situ hybridization, immunohistochemistry, and semiqu antitative reverse-transcription polymerase chain reaction were used to exa mine the expression of mineralization-regulating proteins in human peripher al arteries with and without MS. MS occurred in direct apposition to medial vascular smooth muscle cells (VSMCs) in the absence of macrophages or lipi d. These VSMCs expressed the smooth muscle-specific gene SM22 alpha and hig h levels of matrix Gla protein but little osteopontin mRNA. Compared with n ormal vessels, vessels with MS globally expressed lower levels of matrix Gl a protein and osteonectin, whereas alkaline phosphatase, bone sialoprotein, bone Gla protein, and collagen II, all indicators of osteogenesis/chondrog enesis, were upregulated. Furthermore, VSMCs derived from MS lesions exhibi ted osteoblastic properties and mineralized in vitro. Conclusions-These data indicate that medial calcification in MS lesions is an active process potentially orchestrated by phenotypically modified VSMCs .