MONONUCLEAR LEUKOCYTES INVADE RABBIT ARTERIAL INTIMA DURING THICKENING FORMATION VIA CD18-DEPENDENT AND VLA-4-DEPENDENT MECHANISMS AND STIMULATE SMOOTH-MUSCLE MIGRATION

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 i nhibit leukocyte entry into the arterial intima with antibodies agains t the adhesion molecules very late activation antigen-4, (VLA-4) and C D11/CD18. In electrically stimulated control rabbits treated either wi th saline or a nonspecific antibody, all types of granulocytes, monocy tes, and lymphocytes migrated across an intact endothelium into the ac ellular subendothelial space, followed by the movement of SMCs from th e media into the intima within 36 hours of applying electrical current . Treatment of the rabbits with monoclonal antibody (mAb) HP1/2 direct ed toward the alpha(4) subunit (CD49d) of VLA-4 inhibited mononuclear leukocyte invasion (consisting of monocytes and lymphocytes) by approx imate to 70% compared with the IgG-treated control rabbits and complet ely abolished the minimal influx of basophils and eosinophils after 36 hours, Neutrophil infiltration, however, remained unaffected by anti- VLA-alpha(4) treatment. Under these conditions, SMC migration across t he internal elastic lamina was reduced by 50%. The use of mAb HP1/2 to gether with mAb 60.3 (directed to the beta(2) chain of CD11/CD18) comp letely abolished the influx of monocytes, lymphocytes, and all types o f granulocytes into the arterial intima. This complete blockade of leu kocyte infiltration resulted in a 70% reduction of intimal SMC accumul ation. Together with our previous findings excluding neutrophils as st imulators of SMC migration, the present results indicate that mononucl ear leukocytes promote lesion development by stimulating SMC migration .