Published online before print February 12, 2004, doi: 10.1161/01.RES.0000121105.72718.5C
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Submitted on May 21, 2003
Revised on January 7, 2004
Accepted on January 29, 2004
Neointimal Smooth Muscle Cells Display a Proinflammatory Phenotype Resulting in Increased Leukocyte Recruitment Mediated by P-Selectin and Chemokines
Ute Zeiffer ;
From the Departments of Molecular Cardiovascular Research (U.Z., A.S., M.L., E.L, C.W.) and Cardiology (A.S., C.W.) and from the Institute for Molecular Biotechnology (N.E.); University of Technology, Aachen, Germany; Institute for Prevention of Cardiovascular Diseases (W.E.), Ludwig-Maximilians-University, Munich, Germany, and Center for Molecular Medicine (Z.-q.Y.), Karolinska Institute, Stockholm, Sweden.
* To whom correspondence should be addressed. E-mail: cweber{at}ukaachen.de.
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-
and fractalkine, whereas "memory" T cell arrest was mediated by stromal cell-derived factor (SDF)-1. 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-
B activity, as revealed by immunofluorescence staining for nuclear p65 in vitro. Inhibition of NF-B by adenoviral IB 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-B-mediated proinflammatory phenotype of niSMCs that is characterized by increased P-selectin and chemokine expression and thereby effectively supports leukocyte recruitment.
Key words: restenosis • inflammation • cell adhesion molecules • smooth muscle cells • chemokines
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