on April 21, 2005
Published online before print April 21, 2005, doi: 10.1161/01.ATV.0000166600.58468.1b
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Submitted on September 2, 2004
Accepted on April 7, 2005
Calcification of Advanced Atherosclerotic Lesions in the Innominate Arteries of ApoE-Deficient Mice. Potential Role of Chondrocyte-Like Cells
Marcello Rattazzi ;
From the Department of Pathobiology (M.R., F.B., E.A.K., J.L.R., M.E.R.), the Interdisciplinary Graduate Program in Nutritional Sciences (B.J.B., E.A.K., M.E.R.), the Department of Bioengineering (M.S., C.M.G.), and the Department of Pathology (S.M.S., C.M.G., M.E.R.), University of Washington, Seattle.
* To whom correspondence should be addressed. E-mail: ssmjm{at}u.washington.edu.
Objective--Advanced atherosclerotic lesions in the innominate arteries of chow-fed apolipoprotein E-deficient mice become highly calcified with 100% frequency by 75 weeks of age. The time course, cell types, and mechanism(s) associated with calcification were investigated.
Methods and Results--The deposition of hydroxyapatite is preceded by the formation of fibro-fatty nodules that are populated by cells that morphologically resemble chondrocytes. These cells are spatially associated with small deposits of hydroxyapatite in animals between 45 and 60 weeks of age. Immunocytochemical analyses with antibodies recognizing known chondrocyte proteins show that these cells express the same proteins as chondrocytes within developing bone. Histological and electron microscopic analyses of lesions from animals between 45 and 60 weeks of age show that the chondrocyte-like cells are surrounded by dense connective tissue that stains positive for type II collagen. Nanocrystals of hydroxyapatite can be seen within matrix vesicles derived from the chondrocyte-like cells. In mice between 75 and 104 weeks of age, the lesions have significantly reduced cellularity and contain large calcium deposits. The few remaining chondrocyte-like cells are located adjacent to or within the large areas of calcification.
Conclusions--Calcification of advanced lesions in chow-fed apolipoprotein E-deficient mice occurs reproducibly in mice between 45 and 75 weeks of age. The deposition of hydroxyapatite is mediated by chondrocytes, which suggests that the mechanism of calcification may in part recapitulate the process of endochondral bone formation.
Key words: atherosclerosis • calcification • chondrocytes • apolipoprotein E-deficient mice
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