Published online before print June 9, 2005, doi: 10.1161/01.ATV.0000172687.01179.d4
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© 2005 American Heart Association, Inc.
Vascular Biology |
Platelet, Not Endothelial, P-Selectin Is Required for Neointimal Formation After Vascular Injury
From the Departments of Cardiovascular Medicine (K.W., Z.Z., L.F., A.M.L., E.J.T., M.S.P), Cell Biology (X.Z., N.M., M.Z., M.S.P.), and Molecular Cardiology (E.F.P.), and the Joseph J. Jacobs Center for Thrombosis and Vascular Biology (E.F.P., E.J.T.), Cleveland Clinic Foundation, Cleveland, Ohio.
Correspondence to Kai Wang, MD, PhD, Department of Cardiovascular Medicine/F25, Cleveland Clinic Foundation, 9500 Euclid Ave, Cleveland, OH 44195. E-mail wangk{at}ccf.org
Background— P-selectin blockade significantly inhibits inflammation and neointimal formation after arterial injury; however, the independent roles of platelet and endothelial P-selectins in this process are unknown. In atherosclerosis, both platelet and endothelial cell P-selectins are important. This study was designed to determine whether P-selectin expression on platelet, endothelial, or both surfaces is critical to the inflammatory response and neointimal formation after arterial injury.
Methods and Results— Using wild-type (WT) and P-selectin–knockout (Psel–/–) mice, we performed bone marrow transplantation to generate chimeric mice that expressed either platelet P-selectin (Plt-Psel) or endothelial P-selectin (EC-Psel). Double injury of the carotid artery was performed in these mice as well as in WT and Psel–/– mice. Animals were euthanized 4 or 21 days after arterial injury. Morphometric data showed that there was more neointimal formation in the WT mouse group when compared with the Psel–/– mouse group (0.015±0.004 vs 0.004±0.004 mm2, P<0.001). Further comparison showed significantly less neointimal area in EC-Psel mice (0.006±0.004 mm2) compared with Plt-Psel mice (0.011±0.005 mm2, P=0.026) and WT mice (0.015±0.004 mm2, P=0.001). No significant differences were observed between WT and Plt-Psel mice or between Psel–/– and EC-Psel mice. Decreased neointimal formation was accompanied by a reduced inflammatory response, as evidenced by immunostaining of RANTES and MCP-1 4 days after injury.
Conclusions— Platelet P-selectin expression, but not endothelial P-selectin, plays a crucial role in the development of neointimal formation after arterial injury, and therapeutic strategies targeting leukocyte-platelet interactions could be effective in inhibiting restenosis.
The relative importance of platelet and endothelial P-selectins to neointimal formation after vascular injury was determined by bone marrow transplantation. Significantly less neointima was observed from EC-Psel mice when compared with Plt-Psel mice and WT mice. Decreased neointimal formation was accompanied by reduced inflammation.
Key Words: P-selectin • arterial injury • platelets • endothelial cells • neointima
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