Activation of the UNC5B receptor by Netrin-1 inhibits sprouting angiogenesis

Larrivée, Bruno; Freitas, Catarina; Trombe, Marc; Lv, Xiang; DeLafarge, Benjamin; Li, Yuan; Bouvrée, Karine; Bréant, Christiane; Toro, R.; Bréchot, Nicolas; Germain, Stéphane; Bono, Françoise; Dol, Frédérique; Claes, Filip; Fischer, Christian; Autiero, Monica; Thomas, Jean‐Léon; Carmeliet, Peter; Tessier‐Lavigne, Marc; Eichmann, Anne

doi:10.1101/gad.437807

Cited by 198 publications

(226 citation statements)

References 41 publications

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“…Previous studies have shown that the pro‐ or anti‐angiogenic effects of netrin‐1 depend on its concentration and the receptor it interacts with 37. At high concentrations, netrin‐1 (1000 or 2000 ng/ml) inhibits angiogenesis by binding to the UNC5B receptor, whereas at low concentrations, netrin‐1 (50 or 200 ng/ml) promotes angiogenesis by binding to CD146, suggesting that the role of netrin‐1 may depend on the levels of specific receptors in relation to its own concentration 33, 37. Tu et al .…”

Section: Discussionmentioning

confidence: 99%

CD151 mediates netrin‐1‐induced angiogenesis through the Src‐FAK‐Paxillin pathway

Yang

Zhong

et al. 2016

J Cellular Molecular Medi

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Crosstalk between the nervous and vascular systems is important during development and in response to injury, and the laminin‐like axonal guidance protein netrin‐1 has been studied for its involvement in angiogenesis and vascular remodelling. In this study, we examined the role of netrin‐1 in angiogenesis and explored the underlying mechanisms. The effect of netrin‐1 on brain tissues and endothelial cells was examined by immunohistochemistry and western blotting in a middle cerebral artery occlusion model and in human umbilical vein endothelial cells. Cell proliferation and cell cycle progression were assessed by the MTT assay and flow cytometry, and the Transwell and tube formation assays were used to examine endothelial cell motility and function. Netrin‐1 up‐regulated CD151 and VEGF concomitant with the activation of focal adhesion kinase (FAK), Src and Paxillin in vitro and in vivo and the induction of cell proliferation, migration and tube formation in vitro. Silencing of CD151 abolished the effects of netrin‐1 on promoting cell migration and tube formation mediated by the activation of FAK/Src signalling. Netrin‐1 promoted angiogenesis in vitro and in vivo by activating the FAK/Src/Paxillin signalling pathway through a mechanism dependent on the expression of the CD151 tetraspanin, suggesting the existence of a netrin‐1/FAK/Src/CD151 signalling axis involved in the modulation of angiogenesis.

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Section: Discussionmentioning

confidence: 99%

CD151 mediates netrin‐1‐induced angiogenesis through the Src‐FAK‐Paxillin pathway

Yang

Zhong

et al. 2016

J Cellular Molecular Medi

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“…Likewise, Larrivee et al [28] demonstrated that deletion of the Unc5b gene ameliorates the netrin-1-mediated inhibition of angiogenesis. Netrin-1 repels ECs when UNC5B is expressed, with angiogenesis being suppressed throughout this process.…”

Section: Netrin-1 and Angiogenesismentioning

confidence: 97%

“…It is expressed in the semicircular canals and retina, as well as in the epiphysis, thalamus, and placenta [22][23][24] . UNC5B has been reported to act as a pro-or anti-angiogenic receptor in different studies [25][26][27][28] . DSCAM is a type I transmembrane protein that contains 10 Ig domains and six FNIII repeats in its extracellular domain [19,20] .…”

Section: Receptorsmentioning

confidence: 99%

Axon guidance factor netrin-1 and its receptors regulate angiogenesis after cerebral ischemia

Ding

Liao

2014

Neurosci. Bull.

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Neurogenesis and angiogenesis play important roles in functional recovery after ischemic stroke. When cerebral ischemia occurs, axon regeneration can compensate for the loss of apoptotic neurons in the ischemic area. The formation of new blood vessels ameliorates the local decrease in blood supply, enhancing the supply of oxygen and nutrients to newly-formed neurons. New blood vessels also act as a scaffold for the migration of neuroblasts to the infarct area after ischemic stroke. In light of this, researchers have been actively searching for methods to treat cerebral infarction. Netrins were fi rst identifi ed as a family of proteins that mediate axon guidance and direct axon migration during embryogenesis. Later studies have revealed other functions of this protein family. In this review, we focus on netrin-1, which has been shown to be involved in axon migration and angiogenesis, which are required for recovery after cerebral ischemia. Thus, therapies targeting netrin-1 may be useful for the treatment of ischemic stroke.

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“…This led to the suggestion that Netrin-1 attenuates developmental angiogenesis through the activation of Unc5B. More recently, Larrivée et al (12) provided evidence that Netrin-1 also inhibits postnatal sprouting angiogenesis and neovascularization via the activation of the Unc5B receptor. However, the role of N4 in angiogenesis and its mechanism of action have not been elucidated.…”

mentioning

confidence: 95%

Netrin-4 inhibits angiogenesis via binding to neogenin and recruitment of Unc5B

Lejmi

Leconte

Pédron-Mazoyer

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

130

162

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Netrins are secreted molecules with roles in axon guidance and angiogenesis. We identified Netrin-4 as a gene specifically overexpressed in VEGF-stimulated endothelial cells (EC) in vitro as well as in vivo. Knockdown of Netrin-4 expression in EC increased their ability to form tubular structures on Matrigel. To identify which receptor is involved, we showed by quantitative RT-PCR that EC express three of the six Netrin-1 cognate receptors: neogenin, Unc5B, and Unc5C. In contrast to Netrin-1, Netrin-4 bound only to neogenin but not to Unc5B or Unc5C receptors. Neutralization of Netrin-4 binding to neogenin by blocking antibodies abolished the chemotactic effect of Netrin-4. Furthermore, the silencing of either neogenin or Unc5B abolished Netrin-4 inhibitory effect on EC migration, suggesting that both receptors are essential for its function in vitro. Coimmunoprecipitation experiments demonstrated that Netrin-4 increased the association between Unc5B and neogenin on VEGF-or FGF-2-stimulated EC. Finally, we showed that Netrin-4 significantly reduced pathological angiogenesis in Matrigel and laser-induced choroidal neovascularization models. Interestingly, Netrin-4, neogenin, and Unc5B receptor expression was up-regulated in choroidal neovessel EC after laser injury. Moreover, Netrin-4 overexpression delayed tumor angiogenesis in a model of s.c. xenograft. We propose that Netrin-4 acts as an antiangiogenic factor through binding to neogenin and recruitment of Unc5B.

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Activation of the UNC5B receptor by Netrin-1 inhibits sprouting angiogenesis

Cited by 198 publications

References 41 publications

CD151 mediates netrin‐1‐induced angiogenesis through the Src‐FAK‐Paxillin pathway

CD151 mediates netrin‐1‐induced angiogenesis through the Src‐FAK‐Paxillin pathway

Axon guidance factor netrin-1 and its receptors regulate angiogenesis after cerebral ischemia

Netrin-4 inhibits angiogenesis via binding to neogenin and recruitment of Unc5B

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