Fibrocytes mediate intimal hyperplasia post-vascular injury and are regulated by two tissue factor-dependent mechanisms

D Chen, L Ma, E-L Tham, S Maresh, R I Lechler, J H McVey, A Dorling

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    BACKGROUND: CD34(+) α-smooth muscle actin (SMA)(+) cells mediate intimal hyperplasia (IH) after mechanical endoluminal injury. We previously found that IH is tissue factor (TF) dependent. The precise phenotype of the CD34(+) cells mediating IH is unknown and the mechanisms of TF are also unknown.

    OBJECTIVE: To define the phenotype of cells mediating IH and compare the effects of inhibiting (TF) on different subsets of CD34(+) cells METHODS: Endoluminal injury was induced in C57BL/6 and two strains of mice expressing a human tissue factor pathway inhibitor (hTFPI) fusion protein on different subsets of CD34(+) cells. Confocal microscopy, immunocytofluorescence and real-time PCR were used to determine phenotype.

    RESULTS: Neointimal cells in C57BL/6 mice were defined as a subset of fibrocytes (CD34(+) CD45(+) collagen-1(+) ) expressing SMA, CD31, TIE-2, CXCR4 and CXCL12. Similar cells circulated post-injury and were also found in mice expressing hTFPI on CD34(+) CD31(+) cells, though in these mice, hTFPI inhibited CD31(+) fibrocyte hyperplasia, so no IH developed. Mice with hTFPI on all CD34(+) α-SMA(+) cells repaired arteries back to a pre-injured state. No CD31(+) fibrocytes were found in these mice unless an anti-hTFPI antibody was administered. Similar findings in protease activated receptor (PAR)-1-deficient mice suggested hTFPI prevented thrombin signalling through PAR-1. In vitro, thrombin increased the number of CD31(+) fibrocytes.

    CONCLUSIONS: Inhibition of TF on CD31(+) fibrocytes inhibits IH whereas inhibition on all CD34(+) α-SMA(+) cells (or PAR-1 deficiency) inhibits the appearance of CD31(+) fibrocytes and promotes repair. These data enhance our understanding of IH and suggest novel ways to promote regenerative repair.
    Original languageEnglish
    Pages (from-to)963-974
    Number of pages12
    Issue number5
    Early online date15 Mar 2013
    Publication statusPublished - 15 May 2013


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