(Circulation. 1999;100:2168.)
© 1999 American Heart Association, Inc.
Clinical Investigation and Reports |
Medial Localization of Mineralization-Regulating Proteins in Association With Mönckeberg’s Sclerosis
Evidence for Smooth Muscle Cell–Mediated Vascular Calcification
Presented in part at the 70th Scientific Sessions of the American Heart Association, Orlando, Fla, November 9–12, 1997, and published in abstract form (Circulation. 1997:96[suppl I]:I-666).
From the Department of Medicine, Addenbrooke’s Hospital (C.M.S., D.P., P.L.W.), Cambridge, UK; Papworth Hospital (N.R.B.C.), Papworth-Everard, Cambridgeshire, UK; and the Diabetic Clinic (M.E.E.) and Pathology (J.R.S.), Kings College Hospital, Camberwell, London, UK.
Correspondence to Dr C.M. Shanahan, Department of Medicine, A.C.C.I., Level 6, Box 110, Addenbrooke’s Hospital, Cambridge CB2 2QQ, UK. E-mail cs131{at}mole.bio.cam.ac.uk
Background—Calcification of the media of peripheral arteries is referred to as Mönckeberg’s sclerosis (MS) and occurs commonly in aged and diabetic individuals. Its pathogenesis is unknown, but its presence predicts risk of cardiovascular events and leg amputation in diabetic patients. Several studies have documented expression of bone-associated genes in association with intimal atherosclerotic calcification, leading to the suggestion that vascular calcification may be a regulated process with similarities to developmental osteogenesis. Therefore, we examined gene expression in vessels with MS to determine whether there was evidence for a regulated calcification process in the vessel media.
Methods and Results—In situ hybridization, immunohistochemistry,
and semiquantitative reverse-transcription polymerase chain reaction
were used to examine the expression of mineralization-regulating
proteins in human peripheral arteries with and without MS.
MS occurred in direct apposition to medial vascular smooth muscle cells
(VSMCs) in the absence of macrophages or lipid. These VSMCs
expressed the smooth muscle–specific gene SM22
and high levels of
matrix Gla protein but little osteopontin mRNA. Compared with normal
vessels, vessels with MS globally expressed lower levels of matrix Gla
protein and osteonectin, whereas alkaline phosphatase, bone
sialoprotein, bone Gla protein, and collagen II, all indicators of
osteogenesis/chondrogenesis, were upregulated. Furthermore, VSMCs
derived from MS lesions exhibited 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.
Key Words: osteopontin • proteins • cartilage • muscle, smooth • diabetes mellitus
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