Atherosclerosis and its complications are a major cause of morbidity and mortality in industrialized nations. Although risk factors for atherosclerosis have been identified, the cellular and molecular mechanisms of atherosclerotic lesion initiation are not fully understood. There is increasing evidence that vascular endothelium may play a key role in the pathogenesis of atherosclerosis. This application proposes to study the role of endothelium in regulating one of the earliest events observed in atherogenesis: the adherence of blood monocytes to the arterial luminal surface, a necessary step in their accumulation in the intima and transformation into foam cells. The recent identification by the applicant of a leukocyte adhesion molecule in the rabbit (designated ATHERO-ELAM), which appears to be monocyte-directed, and is expressed selectively by arterial endothelial cells covering early foam cell lesions will allow molecular characterization of monocyte-endothelial interactions during atherogenesis. The primary goals of the proposed research are to (a) characterize the leukocyte adhesive function of ATHERO-ELAM, (b) elucidate its primary structure, (c) determine whether relevant pathophysiologic stimuli including cytokines and native, or altered, serum lipoproteins can upregulate its expression, and (d) identify other endothelial adhesion molecules with similar properties. The characterization of the function of ATHERO-ELAM will utilize monoclonal antibodies to block rabbit monocyte adhesion to cultured endothelial cells and aortic explants. The role of ATHERO-ELAM in the initiation of atherosclerotic lesions will be examined by blocking monocyte adhesion to the arterial lining of genetically hypercholesterolemic rabbits in vivo, and by comparing the temporal and topographic patterns of ATHERO-ELAM expression (determined by immunohistochemical methods) with monocyte adhesion and intimal foam cell accumulation. Finally, molecular cloning of ATHERO-ELAM will reveal its primary structure, define its relationship to known vascular adhesion molecules, and permit future studies examining the relationship of risk factors for atherosclerosis with the regulation of its expression.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL045563-05
Application #
2222246
Study Section
Pathology A Study Section (PTHA)
Project Start
1991-01-01
Project End
1996-06-30
Budget Start
1995-01-01
Budget End
1996-06-30
Support Year
5
Fiscal Year
1995
Total Cost
Indirect Cost
Name
Brigham and Women's Hospital
Department
Type
DUNS #
071723621
City
Boston
State
MA
Country
United States
Zip Code
02115
Vlassara, H; Fuh, H; Donnelly, T et al. (1995) Advanced glycation endproducts promote adhesion molecule (VCAM-1, ICAM-1) expression and atheroma formation in normal rabbits. Mol Med 1:447-56
Walpola, P L; Gotlieb, A I; Cybulsky, M I et al. (1995) Expression of ICAM-1 and VCAM-1 and monocyte adherence in arteries exposed to altered shear stress. Arterioscler Thromb Vasc Biol 15:2-10
Gimbrone Jr, M A; Cybulsky, M I; Kume, N et al. (1995) Vascular endothelium. An integrator of pathophysiological stimuli in atherogenesis. Ann N Y Acad Sci 748:122-31;discussion 131-2
Gurtner, G C; Davis, V; Li, H et al. (1995) Targeted disruption of the murine VCAM1 gene: essential role of VCAM-1 in chorioallantoic fusion and placentation. Genes Dev 9:1-14
Richardson, M; Hadcock, S J; DeReske, M et al. (1994) Increased expression in vivo of VCAM-1 and E-selectin by the aortic endothelium of normolipemic and hyperlipemic diabetic rabbits. Arterioscler Thromb 14:760-9
Cybulsky, M I; Allan-Motamed, M; Collins, T (1993) Structure of the murine VCAM1 gene. Genomics 18:387-91
Li, H; Cybulsky, M I; Gimbrone Jr, M A et al. (1993) An atherogenic diet rapidly induces VCAM-1, a cytokine-regulatable mononuclear leukocyte adhesion molecule, in rabbit aortic endothelium. Arterioscler Thromb 13:197-204
Cybulsky, A V; Stewart, D J; Cybulsky, M I (1993) Glomerular epithelial cells produce endothelin-1. J Am Soc Nephrol 3:1398-404
Ley, K; Baker, J B; Cybulsky, M I et al. (1993) Intravenous interleukin-8 inhibits granulocyte emigration from rabbit mesenteric venules without altering L-selectin expression or leukocyte rolling. J Immunol 151:6347-57
Li, H; Cybulsky, M I; Gimbrone Jr, M A et al. (1993) Inducible expression of vascular cell adhesion molecule-1 by vascular smooth muscle cells in vitro and within rabbit atheroma. Am J Pathol 143:1551-9

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