© 1995 American Heart Association, Inc.
Articles |
Mononuclear Leukocytes Invade Rabbit Arterial Intima During Thickening Formation via CD18- and VLA-4–Dependent Mechanisms and Stimulate Smooth Muscle Migration
From the Pharma Division (D.K., J.F.), Preclinical Research, Hoffmann-La Roche Ltd, Basel, Switzerland; the Division of Hematology (J.M.H.), Department of Medicine, Harborview Medical Center, Seattle, Wash; Biogen Inc (R.R.L.), Cambridge, Mass; and the Institute of Physiology (F.L.), University of Tübingen (Germany).
Correspondence to Dr Dorothee Kling, Pharma Division, Preclinical Research, Hoffmann-La Roche Ltd, CH-4002 Basel, Switzerland. E-mail klingd@roche.com.
Abstract The role of mononuclear leukocytes for the migration
of smooth muscle cells (SMCs) during intimal thickening was
investigated in the rabbit model of electrically stimulated carotid
artery. The approach was to inhibit leukocyte entry into the
arterial intima with antibodies against the adhesion
molecules very late activation antigen-4 (VLA-4) and CD11/CD18. In
electrically stimulated control rabbits treated either with saline or a
nonspecific antibody, all types of granulocytes, monocytes, and
lymphocytes migrated across an intact endothelium into
the acellular subendothelial space, followed by the
movement of SMCs from the media into the intima within 36 hours of
applying electrical current. Treatment of the rabbits with monoclonal
antibody (mAb) HP1/2 directed toward the 
4 subunit
(CD49d) of VLA-4 inhibited mononuclear leukocyte invasion (consisting
of monocytes and lymphocytes) by 
70% compared with the IgG-treated
control rabbits and completely abolished the minimal influx of
basophils and eosinophils after 36 hours. Neutrophil infiltration,
however, remained unaffected by anti–VLA-4 treatment.
Under these conditions, SMC migration across the internal elastic
lamina was reduced by 50%. The use of mAb HP1/2 together with mAb 60.3
(directed to the ß2 chain of CD11/CD18) completely
abolished the influx of monocytes, lymphocytes, and all types of
granulocytes into the arterial intima. This complete
blockade of leukocyte infiltration resulted in a 70% reduction of
intimal SMC accumulation. Together with our previous findings excluding
neutrophils as stimulators of SMC migration, the present results
indicate that mononuclear leukocytes promote lesion development by
stimulating SMC migration.
Key Words: ß1 and ß2 integrins • arteriosclerosis • monocytes • lymphocytes • granulocytes
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