Document Detail

Monocyte chemoattractant protein-1/CCR2 axis promotes vein graft neointimal hyperplasia through its signaling in graft-extrinsic cell populations.
MedLine Citation:
PMID:  22904274     Owner:  NLM     Status:  MEDLINE    
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 (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.
Chunhua Fu; Peng Yu; Ming Tao; Tushar Gupta; Lyle L Moldawer; Scott A Berceli; Zhihua Jiang
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Publication Detail:
Type:  Comparative Study; Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2012-08-16
Journal Detail:
Title:  Arteriosclerosis, thrombosis, and vascular biology     Volume:  32     ISSN:  1524-4636     ISO Abbreviation:  Arterioscler. Thromb. Vasc. Biol.     Publication Date:  2012 Oct 
Date Detail:
Created Date:  2012-09-13     Completed Date:  2013-01-11     Revised Date:  2014-04-10    
Medline Journal Info:
Nlm Unique ID:  9505803     Medline TA:  Arterioscler Thromb Vasc Biol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  2418-26     Citation Subset:  IM    
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MeSH Terms
Carotid Artery, Common / surgery
Cell Proliferation
Cells, Cultured
Chemokine CCL2 / deficiency,  pharmacology,  physiology*
Extracellular Matrix / physiology
Gene Expression Regulation / physiology
Mice, Knockout
Models, Animal
Neointima / pathology*,  physiopathology*
Receptors, CCR2 / deficiency,  physiology*
Signal Transduction / physiology*
Vascular Grafting*
Vena Cava, Inferior / surgery
Grant Support
Reg. No./Substance:
0/Ccl2 protein, mouse; 0/Ccr2 protein, mouse; 0/Chemokine CCL2; 0/Receptors, CCR2

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