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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2001;21:791.)
© 2001 American Heart Association, Inc.

Vascular Biology

Adenosine A_2A Receptor Stimulation Reduces Inflammation and Neointimal Growth in a Murine Carotid Ligation Model

John A. McPherson; Kurt G. Barringhaus; Gregory G. Bishop; John M. Sanders; Jayson M. Rieger; Sean E. Hesselbacher; Lawrence W. Gimple; Eric R. Powers; Timothy Macdonald; Gail Sullivan; Joel Linden; Ian J. Sarembock

From the Cardiovascular Division, Department of Medicine (J.A.M., K.G.B., G.G.B, J.M.S., S.E.H., L.W.G., E.R.P., G.S., J.L., I.J.S.), the Department of Chemistry (J.M.R., T.M.), and the Department of Molecular Physiology and Biological Physics (J.L.), University of Virginia Health System, Charlottesville.

Correspondence to Ian J. Sarembock, MD, Box 158, Cardiovascular Division, University of Virginia Health Systems, Charlottesville, VA 22908. E-mail isarembock{at}virginia.edu

Abstract—Endothelial activation and leukocyte recruitment are early events in atherosclerosis and the vascular response to injury. Adenosine has anti-inflammatory effects on leukocytes and endothelial cells mediated through its A_2A receptor. We tested the hypothesis that A_2A activation would reduce inflammation and neointimal formation in a murine carotid ligation model. Before injury, mice were randomized to a 7-day subcutaneous infusion of a specific A_2A receptor agonist (ATL-146e, 0.004 µg/kg per minute), vehicle control, ATL-146e plus ZM241385 (a selective A_2A antagonist), or ZM241385 alone. Leukocyte recruitment and adhesion molecule expression were assessed at early time points, and the neointimal area was measured at 14 and 28 days after injury. Compared with control mice, ATL-146e–treated mice had significantly less neutrophil and macrophage recruitment and vascular cell adhesion molecule-1, intercellular adhesion molecule-1, and P-selectin expression in the first 7 days after injury. Neointimal area was markedly and persistently reduced by 80% at 14 and 28 days, despite termination of ATL infusion at 7 days. ATL-146e+ZM241385–treated and ZM241385-treated animals had neointimal areas similar to those of control animals, confirming that the observed effects of ATL-146e were mediated specifically by the A_2A receptor. These data demonstrate that novel stimulation of adenosine A_2A receptors can inhibit early inflammatory processes that are important in neointimal formation after vascular injury.

Key Words: adenosine • restenosis • cell adhesion molecules • endothelium • leukocytes

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