© 1999 American Heart Association, Inc.
Original Contribution |
Patterns of Vascular Cell Adhesion Molecule-1 and Intercellular Adhesion Molecule-1 Expression in Rabbit and Mouse Atherosclerotic Lesions and at Sites Predisposed to Lesion Formation
From the Department of Laboratory Medicine and Pathobiology (K.I., L.H., M.I., M.I.C.), University of Toronto and Toronto General Hospital Research Institute, Ontario, Canada, and Vascular Research Division, Department of Pathology (H.L., M.D., B.D.M.), Brigham and Women's Hospital and Harvard Medical School, Boston, Mass.
Correspondence to Myron I. Cybulsky, MD, Department of Laboratory Medicine and Pathobiology, Toronto General Hospital, 200 Elizabeth St, CCRW 1-855, Toronto, Ontario M5G 2C4, Canada. E-mail myron.cybulsky{at}utoronto.ca
Abstract—The recruitment of mononuclear leukocytes and formation of intimal macrophage-rich lesions at specific sites of the arterial tree are key events in atherogenesis. Inducible endothelial cell adhesion molecules may participate in this process. In aortas of normal chow-fed wild-type mice and rabbits, vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1), but not E-selectin, were expressed by endothelial cells in regions predisposed to atherosclerotic lesion formation. En face confocal microscopy of the mouse ascending aorta and proximal arch demonstrated that VCAM-1 expression was increased on the endothelial cell surface in lesion-prone areas. ICAM-1 expression extended into areas protected from lesion formation. Hypercholesterolemia induced atherosclerotic lesion formation in rabbits, LDL receptor and apolipoprotein E knockout mice, and Northern blot analysis demonstrated increased steady-state mRNA levels of VCAM-1 and ICAM-1, but not of E-selectin. Immunohistochemical staining revealed that VCAM-1 and ICAM-1 were expressed predominantly by endothelium in early lesions and by intimal cells in more advanced lesions. In early and advanced lesions, staining was most intense in endothelial cells at and adjacent to lesion borders. ICAM-1 staining extended into the uninvolved aorta. These expression patterns were highly reproducible in both species. The only difference was that VCAM-1 expression in endothelium over the central portions of lesions was found frequently in rabbits and rarely in mice. The expression of VCAM-1 by arterial endothelium in normal animals may represent a pathogenic mechanism or a phenotypic marker of predisposition to atherogenesis.
Key Words: atherosclerosis • endothelium • vascular cell adhesion molecule-1 • intercellular adhesion molecule-1 • expression pattern
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