Neointimal Smooth Muscle Cells Display a Proinflammatory Phenotype Resulting in Increased Leukocyte Recruitment Mediated by P-Selectin and Chemokines

• Published in: Circulation research 2004-04, Vol.94 (6), p.776-784
• Main Authors: Zeiffer, Ute, Schober, Andreas, Lietz, Michael, Liehn, Elisa A, Erl, Wolfgang, Emans, Neil, Yan, Zhong-qun, Weber, Christian
• Format: Article
• Language: English
• Subjects: Animals; Aorta, Thoracic - injuries; Apolipoproteins E - deficiency; Apolipoproteins E - genetics; Arteriosclerosis - metabolism; Arteriosclerosis - pathology; Biological and medical sciences; Cell Adhesion; Cells, Cultured - drug effects; Cells, Cultured - metabolism; Chemokine CX3CL1; Chemokines, CX3C - pharmacology; Chemotaxis, Leukocyte - physiology; Constriction, Pathologic; Cytokines - biosynthesis; Cytokines - genetics; Cytokines - physiology; Endothelium, Vascular - injuries; Fundamental and applied biological sciences. Psychology; Gene Expression Regulation; Hypercholesterolemia - metabolism; I-kappa B Proteins - physiology; Inflammation - metabolism; Inflammation - pathology; Integrin alpha4beta1 - biosynthesis; Integrin alpha4beta1 - genetics; Integrin alpha4beta1 - physiology; Medicin och hälsovetenskap; Membrane Proteins - pharmacology; Mice; Mice, Knockout; Monocytes - cytology; Muscle, Smooth, Vascular - cytology; Muscle, Smooth, Vascular - metabolism; Myocytes, Smooth Muscle - metabolism; NF-kappa B - physiology; NF-KappaB Inhibitor alpha; P-Selectin - biosynthesis; P-Selectin - genetics; P-Selectin - physiology; Rats; Rats, Sprague-Dawley; Receptors, Interleukin-8B - physiology; Recombinant Fusion Proteins - physiology; Recurrence; Rheology; T-Lymphocyte Subsets - cytology; Vertebrates: cardiovascular system
• ISSN: 0009-7330; 1524-4571; 1524-4571
• DOI: 10.1161/01.RES.0000121105.72718.5C

ABSTRACT—Leukocyte recruitment is crucial for the response to vascular injury in spontaneous and accelerated atherosclerosis. Whereas the mechanisms of leukocyte adhesion to endothelium or matrix-bound platelets have been characterized, less is known about the proadhesive role of smooth muscle cells (SMCs) exposed after endothelial denudation. In laminar flow assays, neointimal rat SMCs (niSMCs) supported a 2.5-fold higher arrest of monocytes and “memory” T lymphocytes than medial SMCs, which was dependent on both P-selectin and VLA-4, as demonstrated by blocking antibodies. The increase in monocyte arrest on niSMCs was triggered by the CXC chemokine GRO-α and fractalkine, whereas “memory” T cell arrest was mediated by stromal cell–derived factor (SDF)-1α. This functional phenotype was paralleled by a constitutively increased mRNA and surface expression of P-selectin and of relevant chemokines in niSMCs, as assessed by real-time PCR and flow cytometry. The increased expression of P-selectin in niSMCs versus medial SMCs was associated with enhanced NF-κB activity, as revealed by immunofluorescence staining for nuclear p65 in vitro. Inhibition of NF-κB by adenoviral IκBα in niSMCs resulted in a marked reduction of increased leukocyte arrest in flow. Furthermore, P-selectin expression by niSMCs in vivo was confirmed in a hypercholesterolemic mouse model of vascular injury by double immunofluorescence and by RT-PCR after laser microdissection. In conclusion, we have identified a NF-κB–mediated proinflammatory phenotype of niSMCs that is characterized by increased P-selectin and chemokine expression and thereby effectively supports leukocyte recruitment.