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.

中文翻译：

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巨噬细胞源性Wnt信号增加骨骼肌损伤过程中的内皮通透性。

目的

据报道，炎症反应和巨噬细胞的存在是适当的肌肉再生所必需的。然而，我们对支配巨噬细胞信号促进肌肉再生的分子机制的理解还不完全。

方法与结果

在这里，我们有条件地从巨噬细胞中删除了Wnt分泌所需的Wls，并检查了肌肉损伤后对内皮通透性的影响。BaCl _2后2天，小鼠胫骨前（TA）中Wnt配体和Wls的表达增加受伤。巨噬细胞Wls的丧失抑制了内皮屏障功能的丧失，如通过跨内皮电阻和伊文思蓝染料渗透性测定所测量的。有趣的是，内皮通透性的阻断与降低的VEGF水平相关，并且用VEGFR2阻断抗体预处理野生型内皮细胞足以降低刺激的巨噬细胞上清液诱导的内皮通透性。我们还发现，巨噬细胞Wls-null TA在损伤后7天的横截面积减小，提示肌肉再生延迟。

结论

我们的结果表明，巨噬细胞源性Wnt信号在肌肉损伤后以VEGF依赖性方式增加了内皮通透性。我们的发现暗示巨噬细胞是肌肉损伤后Wnt配体的主要来源，并强调了Wnt途径是损伤后的治疗靶标。