Macrophage Wnt-Calcineurin-Flt1 signaling regulates mouse wound angiogenesis and repair

The treatment of festering wounds is one of the most important aspects of medical care. Macrophages are important components of wound repair, both in fending off infection and in coordinating tissue repair. Here we show that macrophages use a Wnt-Calcineurin-Flt1 signaling pathway to suppress wound...

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Bibliographic Details
Published in:Blood 2013-03, Vol.121 (13), p.2574-2578
Main Authors: Stefater, James A., Rao, Sujata, Bezold, Katie, Aplin, Alfred C., Nicosia, Roberto F., Pollard, Jeffrey W., Ferrara, Napoleone, Lang, Richard A.
Format: Article
Language:English
Subjects:
Animals
Brief Report
Calcineurin - genetics
Calcineurin - metabolism
Cells, Cultured
Dermis - blood supply
Dermis - injuries
Dermis - metabolism
Macrophages - metabolism
Macrophages - physiology
Mice
Mice, Transgenic
Neovascularization, Physiologic - genetics
Protein Subunits - genetics
Protein Subunits - metabolism
Vascular Biology
Vascular Endothelial Growth Factor Receptor-1 - genetics
Vascular Endothelial Growth Factor Receptor-1 - metabolism
Wnt Proteins - genetics
Wnt Proteins - metabolism
Wnt Proteins - physiology
Wnt Signaling Pathway - genetics
Wnt Signaling Pathway - physiology
Wnt-5a Protein
Wound Healing - genetics
Wound Healing - physiology
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Summary:The treatment of festering wounds is one of the most important aspects of medical care. Macrophages are important components of wound repair, both in fending off infection and in coordinating tissue repair. Here we show that macrophages use a Wnt-Calcineurin-Flt1 signaling pathway to suppress wound vasculature and delay repair. Conditional mutants deficient in both Wntless/GPR177, the secretory transporter of Wnt ligands, and CNB1, the essential component of the nuclear factor of activated T cells dephosporylation complex, displayed enhanced angiogenesis and accelerated repair. Furthermore, in myeloid-like cells, we show that noncanonical Wnt activates Flt1, a naturally occurring inhibitor of vascular endothelial growth factor-A–mediated angiogenesis, but only when calcineurin function is intact. Then, as expected, conditional deletion of Flt1 in macrophages resulted in enhanced wound angiogenesis and repair. These results are consistent with the published link between enhanced angiogenesis and enhanced repair, and establish novel therapeutic approaches for treatment of wounds. •Macrophage Wnt signaling regulates wound angiogenesis and repair.
ISSN:0006-4971
1528-0020
DOI:10.1182/blood-2012-06-434621