Robo4 Maintains Vessel Integrity and Inhibits Angiogenesis by Interacting with UNC5B

Koch, Alexander W.; Mathivet, Thomas; Larrivée, Bruno; Tong, Raymond K.; Kowalski, Joe; Pibouin-Fragner, Laurence; Bouvrée, Karine; Stawicki, Scott; Nicholes, Katrina; Rathore, Nisha; Scales, Suzie J.; Luis, Elizabeth; Toro, R.; Freitas, Catarina; Bréant, Christiane; Michaud, Annie; Corvol, Pierre; Thomas, Jean‐Léon; Wu, Yan; Peale, Franklin; Watts, Ryan J.; Tessier‐Lavigne, Marc; Bagri, Anil; Eichmann, Anne

doi:10.1016/j.devcel.2010.12.001

Cited by 186 publications

(224 citation statements)

References 39 publications

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“…Morpholino knockdown of ntn1 (the gene encoding netrin 1) in zebrafish has demonstrated the repulsive guidance activity of netrin 1 for endothelial cells through UNC5B signaling (Lu et al, 2004). However, Ntn1 knockout mice survive until birth and have no vascular abnormalities (Yung et al, 2015), indicating that netrin 1 is not necessarily the only ligand for UNC5B, and an absence of netrin 1 might be compensated for by other ligands in vivo, specifically roundabout homolog 4 or netrin 4 (Koch et al, 2011;Lejmi et al, 2008;Li et al, 2012). Conflicting reports exist regarding the role of netrin 1 as either a pro-angiogenic or antiangiogenic factor (Lu et al, 2004;Larrivée et al, 2007;Wilson et al, 2006;Castets and Mehlen, 2010).…”

Section: Discussionmentioning

confidence: 99%

Placental labyrinth formation in mice requires endothelial FLRT2–UNC5B signaling

et al. 2017

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The placental labyrinth is the interface for gas and nutrient exchange between the embryo and the mother; hence its proper development is essential for embryogenesis. However, the molecular mechanism underlying development of the placental labyrinth, particularly in terms of its endothelial organization, is not well understood. Here, we determined that fibronectin leucine-rich transmembrane protein 2 (FLRT2), a repulsive ligand of the UNC5 receptor family for neurons, is unexpectedly expressed in endothelial cells specifically in the placental labyrinth. Mice lacking FLRT2 in endothelial cells exhibited embryonic lethality at mid-gestation, with systemic congestion and hypoxia. Although they lacked apparent deformities in the embryonic vasculature and heart, the placental labyrinths of these embryos exhibited aberrant alignment of endothelial cells, which disturbed the feto-maternal circulation. Interestingly, this vascular deformity was related to endothelial repulsion through binding to the UNC5B receptor. Our results suggest that the proper organization of the placental labyrinth depends on coordinated inter-endothelial repulsion, which prevents uncontrolled layering of the endothelium.

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Section: Discussionmentioning

confidence: 99%

Placental labyrinth formation in mice requires endothelial FLRT2–UNC5B signaling

et al. 2017

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“…The Slit/Robo family comprises three ligands and four transmembrane receptors and their expressions have been detected in different tissues, such as neuronal tissue (Andrews et al 2007), blood vessels (Jones et al 2008, Koch et al 2011, and the reproductive system (Dickinson et al 2008). The dominant cell types expressing SLIT2/ROBO1 in the human ovary are the granulosa luteal cells and theca luteal cells (Dickinson et al 2008).…”

Section: Discussionmentioning

confidence: 99%

“…The Slit/Robo family regulates cell fate, including migration, death, angiogenesis, and organogenesis (Wu et al 2001, Park et al 2003, Dickinson et al 2004, Hinck 2004, Koch et al 2011. It has been documented that Slit/Robo suppresses the development of cancers by inhibiting cell migration and promoting apoptosis (Dickinson et al 2008), and both Slits and Robos are inactivated in several tumors including cervical, prostatic, and ovarian tumors (Latil et al 2003, Singh et al 2007, Dai et al 2011.…”

Section: Introductionmentioning

confidence: 99%

Prostaglandin F2 α upregulates Slit/Robo expression in mouse corpus luteum during luteolysis

Zhang¹,

Li²,

Liu³

et al. 2013

Journal of Endocrinology

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Prostaglandin F 2a (PGF 2a ) is a key factor in the triggering of the regression of the corpus luteum (CL). Furthermore, it has been reported that Slit/Robo signaling is involved in the regulation of luteolysis. However, the interactions between PGF 2a and Slit/Robo in the progression of luteolysis remain to be established. This study was designed to determine whether luteolysis is regulated by the interactions of PGF 2a and Slit/Robo in the mouse CL. Real-time PCR and immunohistochemistry results showed that Slit2 and its receptor Robo1 are highly and specifically co-expressed in the mouse CL. Functional studies showed that Slit/Robo participates in mouse luteolysis by enhancing cell apoptosis and upregulating caspase3 expression. Both in vitro and in vivo studies showed that PGF 2a significantly increases the expression of Slit2 and Robo1 during luteolysis through protein kinase C-dependent ERK1/2 and P38 MAPK signaling pathways, whereas an inhibitor of Slit/Robo signaling significantly decreases the stimulating effect of PGF 2a on luteolysis. These findings indicate that Slit/Robo signaling plays important roles in PGF 2a -induced luteolysis by mediating the PGF 2a signaling pathway in the CL.

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“…23,25 The Robo4/Slit2 signaling pathway has recently been identified as a regulator of microvascular maturation, endothelial permeability, and angiogenesis. [67][68][69] Our ongoing studies suggest that Robo4 protein is significantly decreased in the cerebral microvasculature of diabetic GK rats that develop erratic and dysfunctional angiogenesis (unpublished data). Interestingly, crosstalk between VEGF receptor tyrosine kinases and integrin signaling has been reported.…”

Section: Diabetes and Neovascularizationmentioning

confidence: 99%

Cerebral Neovascularization in Diabetes: Implications for Stroke Recovery and beyond

Ergul

Abdelsaid

Fouda

et al. 2014

J Cereb Blood Flow Metab

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Neovascularization is an innate physiologic response by which tissues respond to various stimuli through collateral remodeling (arteriogenesis) and new vessel formation from existing vessels (angiogenesis) or from endothelial progenitor cells (vasculogenesis). Diabetes has a major impact on the neovascularization process but the response varies between different organ systems. While excessive angiogenesis complicates diabetic retinopathy, impaired neovascularization contributes to coronary and peripheral complications of diabetes. How diabetes influences cerebral neovascularization remained unresolved until recently. Diabetes is also a major risk factor for stroke and poor recovery after stroke. In this review, we discuss the impact of diabetes, stroke, and diabetic stroke on cerebral neovascularization, explore potential mechanisms involved in diabetes-mediated neovascularization as well as the effects of the diabetic milieu on poststroke neovascularization and recovery, and finally discuss the clinical implications of these effects.

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Robo4 Maintains Vessel Integrity and Inhibits Angiogenesis by Interacting with UNC5B

Cited by 186 publications

References 39 publications

Placental labyrinth formation in mice requires endothelial FLRT2–UNC5B signaling

Placental labyrinth formation in mice requires endothelial FLRT2–UNC5B signaling

Prostaglandin F2 α upregulates Slit/Robo expression in mouse corpus luteum during luteolysis

Cerebral Neovascularization in Diabetes: Implications for Stroke Recovery and beyond

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