Macrophage-derived Wnt signaling increases endothelial permeability during skeletal muscle injury

Inflamm Res. 2020 Dec;69(12):1235-1244. doi: 10.1007/s00011-020-01397-z. Epub 2020 Sep 9.


Objective: The inflammatory response and the presence of macrophages are reported to be necessary for proper muscle regeneration. However, our understanding of the molecular mechanisms governing how macrophages signal to promote muscle regeneration is incomplete.

Methods and results: Here we conditionally deleted Wls, which is required for Wnt secretion, from macrophages and examined the impact on endothelial permeability following muscle injury. The expression of Wnt ligands and Wls was increased in the tibialis anterior (TA) of mice 2 days following BaCl2 injury. Loss of macrophage Wls inhibited the loss of endothelial barrier function, as measured by transendothelial resistance and Evans blue dye permeability assays. Interestingly, the blockade in endothelial permeability correlated with reduced VEGF levels and pretreatment of wild type endothelial cells with a VEGFR2 blocking antibody was sufficient to reduce endothelial permeability induced by stimulated macrophage supernatant. We also found that macrophage Wls-null TAs had myocytes with reduced cross-sectional area 7 day post-injury suggesting a delay in muscle regeneration.

Conclusion: Our results indicate that macrophage-derived Wnt signaling increases endothelial permeability in a VEGF-dependent fashion following muscle injury. Our findings implicate macrophages as a primary source of Wnt ligands following muscle injury and highlight the Wnt pathway as a therapeutic target following injury.

Keywords: Endothelial; Macrophage; Permeability; Skeletal muscle; Wnt.

MeSH terms

  • Animals
  • Antibodies, Blocking / pharmacology
  • Cells, Cultured
  • Endothelial Cells / pathology
  • Endothelium / pathology*
  • Humans
  • Macrophages / pathology*
  • Mice
  • Mice, Knockout
  • Muscle, Skeletal / injuries*
  • Muscle, Skeletal / pathology*
  • Permeability
  • Regeneration
  • Vascular Endothelial Growth Factor A / genetics
  • Vascular Endothelial Growth Factor A / metabolism
  • Vascular Endothelial Growth Factor Receptor-2 / antagonists & inhibitors
  • Wnt Signaling Pathway*
  • Wound Healing


  • Antibodies, Blocking
  • Vascular Endothelial Growth Factor A
  • vascular endothelial growth factor A, mouse
  • Kdr protein, mouse
  • Vascular Endothelial Growth Factor Receptor-2