© 2001 American Heart Association, Inc.
Cellular Biology |
Cellular Pathology of Atherosclerosis
Smooth Muscle Cells Prime Cocultured Endothelial Cells for Enhanced Leukocyte Adhesion
From the Department of Physiology, The Medical School, The University of Birmingham, UK.
Correspondence to Dr G.E. Rainger, Department of Physiology, The Medical School, The University of Birmingham, B15 2TT, UK. E-mail g.e.rainger{at}bham.ac.uk
Abstract— During
the development of an atherosclerotic plaque, mononuclear leukocytes
infiltrate the artery wall through vascular endothelial
cells (ECs). At the same time, arterial smooth muscle cells
(SMCs) change from the physiological contractile
phenotype to the secretory phenotype and migrate into
the plaque. We investigated whether secretory SMCs released
cytokines that stimulated ECs in a manner leading to increased
leukocyte recruitment and thus might accelerate atheroma
formation. SMCs and ECs were established in coculture on the opposite
sides of a porous membrane, and the cocultured cells were incorporated
into a flow-based assay for studying leukocyte adhesion. We found that
coculture primed ECs so that their response to the inflammatory
cytokine tumor necrosis factor-
was amplified. ECs
cocultured with SMCs supported greatly increased adhesion of flowing
leukocytes and were sensitized to respond to tumor necrosis factor-
at concentrations 10 000 times lower than ECs cultured alone. In
addition, coculture altered the endothelial selectin
adhesion molecules used for leukocyte capture. EC priming was
attributable to the cytokine transforming growth
factor-ß1, which was proteolytically
activated to a biologically active form by the serine protease
plasmin. These results suggest a new role for secretory SMCs in the
development of atheromatous plaque. We propose that
paracrine interaction between ECs and SMCs has the potential to amplify
leukocyte recruitment to sites of atheroma and exacerbate
the inflammatory processes believed to be at the heart of disease
progression.
Key Words: endothelial cells • smooth muscle cells • leukocyte adhesion • transforming growth factor-ß1 • tumor necrosis factor-
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