title: Macrophage Wnt-Calcineurin-Flt1 signaling regulates mouse wound angiogenesis and repair.
abstract: 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.
authors.affiliation: The Visual Systems Group, Divisions of Pediatric Ophthalmology and Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
authors.forename: James A
authors.initials: JA
authors.lastname: Stefater
authors.forename: Sujata
authors.initials: S
authors.lastname: Rao
authors.forename: Katie
authors.initials: K
authors.lastname: Bezold
authors.forename: Alfred C
authors.initials: AC
authors.lastname: Aplin
authors.forename: Roberto F
authors.initials: RF
authors.lastname: Nicosia
authors.forename: Jeffrey W
authors.initials: JW
authors.lastname: Pollard
authors.forename: Napoleone
authors.initials: N
authors.lastname: Ferrara
authors.forename: Richard A
authors.initials: RA
authors.lastname: Lang
mesh_terms: D000818:Animals; D019703:Calcineurin / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D020405:Dermis / Q000098:blood supply / Q000293:injuries / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism* / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D018919:Neovascularization, Physiologic / Q000235:genetics; D021122:Protein Subunits / Q000235:genetics / Q000378:metabolism; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000235:genetics / Q000378:metabolism*; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D060449:Wnt Signaling Pathway / Q000235:genetics / Q000502:physiology*; D000071818:Wnt-5a Protein; D014945:Wound Healing / Q000235:genetics / Q000502:physiology
chemical_list: D021122:Protein Subunits; D051153:Wnt Proteins; D000071818:Wnt-5a Protein; C438615:Wnt5a protein, mouse; C501163:Flt1 protein, mouse; D040281:Vascular Endothelial Growth Factor Receptor-1; D019703:Calcineurin