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.


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 (graft-extrinsic group) the vein wall. 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.


CONCLUSIONS
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.
Department of Surgery, University of Florida College of Medicine, Gainesville, FL, USA.
Chunhua
C
Fu
Peng
P
Yu
Ming
M
Tao
Tushar
T
Gupta
Lyle L
LL
Moldawer
Scott A
SA
Berceli
Zhihua
Z
Jiang
D000818:Animals; D017536:Carotid Artery, Common / Q000601:surgery; D049109:Cell Proliferation; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000172:deficiency / Q000494:pharmacology / Q000502:physiology*; D005109:Extracellular Matrix / Q000502:physiology; D005786:Gene Expression Regulation / Q000502:physiology; D006965:Hyperplasia; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D023421:Models, Animal; D058426:Neointima / Q000473:pathology* / Q000503:physiopathology*; D054390:Receptors, CCR2 / Q000172:deficiency / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D058017:Vascular Grafting; D014682:Vena Cava, Inferior / Q000601:surgery
C491768:Ccl2 protein, mouse; C515335:Ccr2 protein, mouse; D018932:Chemokine CCL2; D054390:Receptors, CCR2