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

Stefater, James A.; Rao, Sujata; Bezold, Katie; Aplin, Alfred C.; Nicosia, Roberto F.; Pollard, Jeffrey W.; Ferrara, Napoleone; Lang, Richard A.

doi:10.1182/blood-2012-06-434621

Cited by 58 publications

(41 citation statements)

References 39 publications

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“…Consistent with this, deletion of VEGF expression in macrophages severely reduced angiogenesis in open murine excisional wounds [84]; however, more recent studies indicate that macrophages can also have a "dampening" role on wound angiogenesis via noncanonical Wnt signalling and activation of Flt1 (a non-signalling VEGF receptor), which acts to suppress VEGF-mediated angiogenesis [85]. Also, a study in RhoB null mice showed that this non-constitutively expressed small GTPase, acting via VEZF1, is necessary for wound blood vessel sprouting, and that coincident with reduced wound angiogenesis in KO mouse wounds, there was enhanced lymphangiogenesis, which is normally much delayed by comparison to blood vessel sprouting [86].…”

Section: Wound Angiogenesismentioning

confidence: 68%

Wound repair: a showcase for cell plasticity and migration

Shaw

Martin

2016

Current Opinion in Cell Biology

183

143

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A skin wound requires several cell lineages to exhibit considerable plasticity as they migrate towards and over the site of damage to contribute to repair. The keratinocytes that re-epithelialize the tissue, the dermal fibroblasts and potentially other mesenchymal stem cell populations that repopulate damaged connective tissue, the immune cells that counter infections, and endothelial cells that re-establish blood supply and facilitate the immune response -all of these cells are "dynamic" in that they are activated by immediate wound cues, they reprogram to adopt cell behaviours essential for repair including migration, and finally they must resolve. In adult tissues, repair is unique in its requirement for dramatic cell changes and movements otherwise associated only with development and disease.

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Section: Wound Angiogenesismentioning

confidence: 68%

Wound repair: a showcase for cell plasticity and migration

Shaw

Martin

2016

Current Opinion in Cell Biology

183

143

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“…The importance of Wnt ligands as developmental regulators of cell proliferation, migration, differentiation, and polarity are well known. In addition, recent reports suggest inhibitory roles of myeloid derived Wnt5a in developmental angiogenesis and wound repair (24,47). Surprisingly, Wnt5a was highly expressed in ischemic hind limb muscle of Glrx TG compared with WT control.…”

Section: Discussionmentioning

confidence: 97%

“…In myeloid cells, Wnt5a induction of sFlt is likely through nuclear factor of activated T cells (NFAT) activation (47). Interestingly, the interaction between NFAT and NF-B p65 promotes synergistic activation of NFAT (54).…”

Section: Discussionmentioning

confidence: 99%

Glutaredoxin-1 Up-regulation Induces Soluble Vascular Endothelial Growth Factor Receptor 1, Attenuating Post-ischemia Limb Revascularization

Murdoch

Shuler

Haeussler

et al. 2014

Journal of Biological Chemistry

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Background: Glutaredoxin-1 (Glrx) inhibits endothelial cell migration by reversing protein-glutathione adducts. Results: Revascularization after hind limb ischemia was inhibited in Glrx transgenic mice. Glrx overexpression increased soluble VEGF receptor 1 (sFlt) in endothelial cells via NF-B-dependent Wnt5a production. Conclusion: Glrx enhances Wnt5a-induced anti-angiogenic sFlt in endothelial cells. Significance: Up-regulated Glrx inhibits VEGF signaling by increased sFlt causing impaired vascularization.

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“…By contrast, evidence for noncanonical Wnt signaling during angiogenesis is only beginning to emerge (Masckauchan et al, 2006;Cirone et al, 2008;Descamps et al, 2012). On the one hand, non-canonical Wnt ligands have been shown to suppress angiogenesis during retinal vascularization and wound healing (Stefater et al, 2011(Stefater et al, , 2013. On the other hand, Wnt5a has been described as a pro-angiogenic factor promoting EC proliferation, migration, survival and network formation (Masckauchan et al, 2006;Cirone et al, 2008;Descamps et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

Endothelial cell-derived non-canonical Wnt ligands control vascular pruning in angiogenesis

et al. 2014

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Multiple cell types involved in the regulation of angiogenesis express Wnt ligands. Although β-catenin dependent and independent Wnt signaling pathways have been shown to control angiogenesis, the contribution of individual cell types to activate these downstream pathways in endothelial cells (ECs) during blood vessel formation is still elusive. To investigate the role of ECs in contributing Wnt ligands for regulation of blood vessel formation, we conditionally deleted the Wnt secretion factor Evi in mouse ECs (Evi-ECKO). Evi-ECKO mice showed decreased microvessel density during physiological and pathological angiogenesis in the postnatal retina and in tumors, respectively. The reduced microvessel density resulted from increased vessel regression accompanied by decreased EC survival and proliferation. Concomitantly, survival-related genes were downregulated and cell cycle arrest-and apoptosis-inducing genes were upregulated. EVI silencing in cultured HUVECs showed similar target gene regulation, supporting a mechanism of EC-derived Wnt ligands in controlling EC function. ECs preferentially expressed non-canonical Wnt ligands and canonical target gene expression was unaffected in Evi-ECKO mice. Furthermore, the reduced vascularization of Matrigel plugs in Evi-ECKO mice could be rescued by introduction of non-canonical Wnt5a. Treatment of mouse pups with the non-canonical Wnt inhibitor TNP470 resulted in increased vessel regression accompanied by decreased EC proliferation, thus mimicking the proliferation-dependent Evi-ECKO remodeling phenotype. Taken together, this study identified EC-derived non-canonical Wnt ligands as regulators of EC survival, proliferation and subsequent vascular pruning during developmental and pathological angiogenesis.

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

Abstract: Key Points Macrophage Wnt signaling regulates wound angiogenesis and repair.

Cited by 58 publications

References 39 publications

Wound repair: a showcase for cell plasticity and migration

Wound repair: a showcase for cell plasticity and migration

Glutaredoxin-1 Up-regulation Induces Soluble Vascular Endothelial Growth Factor Receptor 1, Attenuating Post-ischemia Limb Revascularization

Endothelial cell-derived non-canonical Wnt ligands control vascular pruning in angiogenesis

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