Monocyte Chemoattractant Protein-1/CCR2 Axis Promotes Vein Graft Neointimal Hyperplasia Through Its Signaling in Graft-Extrinsic Cell Populations
Objective—To evaluate direct versus indirect monocyte chemoattractant protein (MCP)-1/CCR2 signaling and to identify the cellular producers and effectors for MCP-1 during neointimal hyperplasia (NIH) development in vein grafts.
Methods and Results—Genomic analysis revealed an overrepresentation of 13 inflammatory pathways in wild-type vein grafts compared with CCR2 knockout vein grafts. Further investigation with various vein graft–host combinations of MCP-1- and CCR2-deficient mice was used to modify the genotype of cells both inside (graft-intrinsic group) and outside the vein wall (graft-extrinsic group). CCR2 deficiency inhibited NIH only when present in cells extrinsic to the graft wall, and MCP-1 deficiency required its effectiveness in cells both intrinsic and extrinsic to the graft wall to suppress NIH. Deletion of either MCP-1 or CCR2 was equally effective in inhibiting NIH. CCR2 deficiency in the predominant neointimal cell population had no impact on NIH. Direct MCP-1 stimulation of primary neointimal smooth muscle cells had minimal influence on cell proliferation and matrix turnover, confirming an indirect mechanism of action.
Conclusion—MCP-1/CCR2 axis accelerates NIH via its signaling in graft-extrinsic cells, particularly circulating inflammatory cells, with cells both intrinsic and extrinsic to the graft wall being critical MCP-1 producers. These findings underscore the importance of systemic treatment for anti–MCP-1/CCR2 therapies.
- Received October 26, 2011.
- Accepted July 30, 2012.
- © 2012 American Heart Association, Inc.