Advanced studies on the role of Slit2-Robo signaling in angiogenesis of fundus oculi and some other organs_Chinese Journal of Ocular Fundus Diseases

Authors：

Jiang Shaoqiu , Liu Danning ,  Zhou Xiyuan

Department of Ophthalmology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, China;

Corresponding author：

Zhou Xiyuan, Email: zhouxiyuan2002@aliyun.com

Keywords：

Slit2-Robo signaling; Fundus oculi; Angiogenesis; Neovascularization, pathologic; Review

DOI：

10.3760/cma.j.issn.1005-1015.2018.03.026

Video：

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Axon guidance molecules, slit glycoprotein (Slit) and Roundabout receptors (Robo) were firstly identified in the central neural system of Drosophila melanogaster. The Slit-Robo signal plays a crucial role in axon guidance, inflammation, tumor metastasis and angiogenesis, of which the role of Slit2-Robo pathway in angiogenesis has drawn a greater attention and still remains conflicting. Herein, we provide a review on the role of Slit2-Robo pathway in ocular angiogenesis and vascularization of other organs and systems. We hope this review will be the basis of further study on the mechanism of Slit2-Robo signaling on angiogenesis and provide new target for the therapy on ocular vascular disease

Citation： Jiang Shaoqiu, Liu Danning, Zhou Xiyuan. Advanced studies on the role of Slit2-Robo signaling in angiogenesis of fundus oculi and some other organs. Chinese Journal of Ocular Fundus Diseases, 2018, 34(3): 308-311. doi: 10.3760/cma.j.issn.1005-1015.2018.03.026 Copy

1.	Brose K, Bland KS, Wang KH, et al. Slit proteins bind Robo receptors and have an evolutionarily conserved role in repulsive axon guidance[J]. Cell, 1999, 96(6): 795-806.
2.	Hu H. Cell-surface heparan sulfate is involved in the repulsive guidance activities of Slit2 protein[J]. Nat Neurosci, 2001, 4(7): 695-701. DOI: 10.1038/89482.
3.	Dickson BJ, Gilestro GF. Regulation of commissural axon pathfinding by slit and its Robo receptors[J]. Annu Rev Cell Dev Biol, 2006, 22: 651-675. DOI: 10.1146/annurev.cellbio.21.090704.151234.
4.	Li J, Ye Y, Zhang R, et al. Robo1/2 regulate follicle atresia through manipulating granulosa cell apoptosis in mice[J]. Sci Rep, 2015, 5: 9720. DOI: 10.1038/srep09720.
5.	Fujiwara K, Koyama K, Suga K, et al. 90Y-labeled anti-ROBO1 monoclonal antibody exhibits antitumor activity against small cell lung cancer xenografts[J/OL]. PLoS One, 2015, 10(5): 0125468[2015-05-27]. https://doi.org/10.1371/journal.pone.0125468. DOI: 10.1371/journal.pone.0125468.
6.	Zhang QQ, Zhou DL, Lei Y, et al. Slit2/Robo1 signaling promotes intestinal tumorigenesis through Src-mediated activation of the Wnt/β-catenin pathway[J]. Oncotarget, 2015, 6(5): 3123-3135. DOI: 10.18632/oncotarget.3060.
7.	Zhao H, Ahirwar DK, Oghumu S, et al. Endothelial Robo4 suppresses breast cancer growth and metastasis through regulation of tumor angiogenesis[J]. Mol Oncol, 2016, 10(2): 272-281. DOI: 10.1016/j.molonc.2015.10.007.
8.	Rama N, Dubrac A, Mathivet T, et al. Slit2 signaling through Robo1 and Robo2 is required for retinal neovascularization[J]. Nat Med, 2015, 21(5): 483-491. DOI: 10.1038/nm.3849.
9.	Guijarro-Muñoz I, Cuesta AM, Alvarez-Cienfuegos A, et al. The axonal repellent Slit2 inhibits pericyte migration: potential implications in angiogenesis[J]. Exp Cell Res, 2012, 318(4): 371-378. DOI: 10.1016/j.yexcr.2011.12.005.
10.	Anand AR, Zhao H, Nagaraja T, et al. N-terminal Slit2 inhibits HIV-1 replication by regulating the actin cytoskeleton[J]. Retrovirology, 2013, 10: 2. DOI: 10.1186/1742-4690-10-2.
11.	Fritz RD, Menshykau D, Martin K, et al. SrGAP2-dependent integration of membrane geometry and Slit-Robo-repulsive cues regulates fibroblast contact inhibition of locomotion[J]. Dev Cell, 2015, 35(1): 78-92. DOI: 10.1016/j.devcel.2015.09.002.
12.	Enomoto S, Mitsui K, Kawamura T, et al. Suppression of Slit2/Robo1 mediated HUVEC migration by Robo4[J]. Biochem Biophys Res Commun, 2016, 469(4): 797-802. DOI: 10.1016/j.bbrc.2015.12.075.
13.	Yang YC, Chen PN, Wang SY, et al. The differential roles of Slit2-exon 15 splicing variants in angiogenesis and HUVEC permeability[J]. Angiogenesis, 2015, 18(3): 301-312. DOI: 10.1007/s10456-015-9467-4.
14.	Liu D, Hou J, Hu X, et al. Neuronal chemorepellent Slit2 inhibits vascular smooth muscle cell migration by suppressing small GTPase Rac1 activation[J]. Circ Res, 2006, 98(4): 480-489. DOI: 10.1161/01.RES.0000205764.85931.4b.
15.	Ning Y, Sun Q, Dong Y, et al. Slit2-N inhibits PDGF-induced migration in rat airway smooth muscle cells: WASP and Arp2/3 involved[J]. Toxicology, 2011, 283(1): 32-40. DOI: 10.1016/j.tox.2011.01.026.
16.	Bartel DP. MicroRNAs: genomics, biogenesis, mechanism, and function[J]. Cell, 2004, 116(2): 281-297.
17.	Small EM, Frost RJ, Olson EN. MicroRNAs add a new dimension to cardiovascular disease[J]. Circulation, 2010, 121(8): 1022-1032. DOI: 10.1161/CIRCULATIONAHA.109.889048.
18.	Gu JJ, Gao GZ, Zhang SM. miR-218 inhibits the migration and invasion of glioma U87 cells through the Slit2-Robo1 pathway[J]. Oncol Lett, 2015, 9(4): 1561-1566. DOI: 10.3892/ol.2015.2904.
19.	Punnamoottil B, Rinkwitz S, Giacomotto J, et al. Motor neuron-expressed microRNAs 218 and their enhancers are nested within introns of Slit2/3 genes[J]. Genesis, 2015, 53 (5): 321-328. DOI: 10.1002/dvg.22852.
20.	Tang W, Tang J, He J, et al. SLIT2/ROBO1-miR-218-1-RET/PLAG1: a new disease pathway involved in Hirschsprung’s disease[J]. J Cell Mol Med, 2015, 19(6): 1197-1207. DOI: 10.1111/jcmm.12454.
21.	Small EM, Sutherland LB, Rajagopalan KN, et al. MicroRNA-218 regulates vascular patterning by modulation of Slit-Robo signaling[J]. Circ Res, 2010, 107(11): 1336-1344. DOI: 10.1161/CIRCRESAHA.110.227926.
22.	Kong Y, Sun B, Han Q, et al. Slit-miR-218-Robo axis regulates retinal neovascularization [J]. Int J Mol Med, 2016, 37(4): 1139-1145.DOI: 10.3892/ijmm.2016.2511.
23.	Han S, Kong YC, Sun B, et al. microRNA-218 inhibits oxygen-induced retinal neovascularization via reducing the expression of roundabout 1[J]. Chin Med J (Engl), 2016, 129(6): 709-715. DOI: 10.4103/0366-6999.178013.
24.	Yu J, Zhang X, Kuzontkoski PM, et al. Slit2N and Robo4 regulate lymphangiogenesis through the VEGF-C/VEGFR-3 pathway[J]. Cell Commun Signal, 2014, 12: 25. DOI: 10.1186/1478-811X-12-25.
25.	Youngblood V, Wang S, Song W, et al. Elevated Slit2 activity impairs VEGF-induced angiogenesis and tumor neovascularization in EphA2-deficient endothelium[J]. Mol Cancer Res, 2015, 13(3): 524-537. DOI: 10.1158/1541-7786.MCR-14-0142.
26.	Cai H, Xue Y, Li Z, et al. Roundabout4 suppresses glioma-induced endothelial cell proliferation, migration and tube formation in vitro by inhibiting VEGR2-mediated PI3K/AKT and FAK signaling pathways[J]. Cell Physiol Biochem, 2015, 35(5): 1689-1705. DOI: 10.1159/000373982.
27.	Ao JY, Chai ZT, Zhang YY, et al. Robo1 promotes angiogenesis in hepatocellular carcinoma through the Rho family of guanosine triphosphatases' signaling pathway[J]. Tumour Biol, 2015, 36(11): 8413-8424. DOI: 10.1007/s13277-015-3601-1.
28.	Wang B, Xiao Y, Ding BB, et al. Induction of tumor angiogenesis by Slit-Robo signaling and inhibition of cancer growth by blocking Robo activity[J]. Cancer Cell, 2003, 4(1): 19-29.
29.	Liao WX, Laurent LC, Agent S, et al. Human placental expression of SLIT/ROBO signaling cues: effects of preeclampsia and hypoxia[J]. Biol Reprod, 2012, 86(4): 111. DOI: 10.1095/biolreprod.110.088138.
30.	Guo SW, Zheng Y, Lu Y, et al. Slit2 overexpression results in increased microvessel density and lesion size in mice with induced endometriosis[J]. Reprod Sci, 2013, 20(3): 285-298. DOI: 10.1177/1933719112452940.
31.	Li P, Peng H, Lu WH, et al. Role of Slit2/Robo1 in trophoblast invasion and vascular remodeling during ectopic tubal pregnancy[J]. Placenta, 2015, 36(10): 1087-1094. DOI: 10.1016/j.placenta.2015.08.002.
32.	Han HX, Geng JG. Over-expression of Slit2 induces vessel formation and changes blood vessel permeability in mouse brain[J]. Acta Pharmacol Sin, 2011, 32(11): 1327-1336. DOI: 10.1038/aps.2011.106.
33.	Nieminen T, Toivanen PI, Laakkonen JP, et al. Slit2 modifies VEGF-induced angiogenic responses in rabbit skeletal muscle via reduced eNOS activity[J]. Cardiovasc Res, 2015, 107(2): 267-276. DOI: 10.1093/cvr/cvv161.
34.	Jones CA, London NR, Chen H, et al. Robo4 stabilizes the vascular network by inhibiting pathologic angiogenesis and endothelial hyperpermeability[J]. Nat Med, 2008, 14(4): 448-453. DOI: 10.1038/nm1742.
35.	Li S, Huang L1, Sun Y, et al.Slit2 promotes angiogenic activity via the robo1- VEGFR2- ERK1/2 pathway in both in vivo and in vitro studies[J].Invest Ophthalmol Vis Sci, 2015, 56(9): 5210-5217. DOI: 10.1167/iovs-14-16184.
36.	Farnoodian M, Halbach C, Slinger C, et al. High glucose promotes the migration of retinal pigment epithelial cells through increased oxidative stress and PEDF expression[J]. Am J Physiol Cell Physiol, 2016, 311(3): 418-436. DOI: 10.1152/ajpcell.00001.2016.
37.	Huang L, Xu Y, Yu W, et al. Effect of Robo1 on retinal pigment epithelial cells and experimental proliferative vitreoretinopathy[J]. Invest Ophthalmol Vis Sci, 2010, 51 (6): 3193-3204. DOI: 10.1167/iovs.09-3779.
38.	Zhou W, Yu W, Xie W, et al. The role of SLIT-ROBO signaling in proliferative diabetic retinopathy and retinal pigment epithelial cells[J]. Mol Vis, 2011, 17: 1526-1536.
39.	Dubrac A, Genet G, Ola R, et al. Targeting NCK-mediated endothelial cell front-rear polarity inhibits neovascularization[J]. Circulation, 2016, 133(4): 409-421. DOI: 10.1161/CIRCULATIONAHA.115.017537.

1. Brose K, Bland KS, Wang KH, et al. Slit proteins bind Robo receptors and have an evolutionarily conserved role in repulsive axon guidance[J]. Cell, 1999, 96(6): 795-806.
2. Hu H. Cell-surface heparan sulfate is involved in the repulsive guidance activities of Slit2 protein[J]. Nat Neurosci, 2001, 4(7): 695-701. DOI: 10.1038/89482.
3. Dickson BJ, Gilestro GF. Regulation of commissural axon pathfinding by slit and its Robo receptors[J]. Annu Rev Cell Dev Biol, 2006, 22: 651-675. DOI: 10.1146/annurev.cellbio.21.090704.151234.
4. Li J, Ye Y, Zhang R, et al. Robo1/2 regulate follicle atresia through manipulating granulosa cell apoptosis in mice[J]. Sci Rep, 2015, 5: 9720. DOI: 10.1038/srep09720.
5. Fujiwara K, Koyama K, Suga K, et al. 90Y-labeled anti-ROBO1 monoclonal antibody exhibits antitumor activity against small cell lung cancer xenografts[J/OL]. PLoS One, 2015, 10(5): 0125468[2015-05-27]. https://doi.org/10.1371/journal.pone.0125468. DOI: 10.1371/journal.pone.0125468.
6. Zhang QQ, Zhou DL, Lei Y, et al. Slit2/Robo1 signaling promotes intestinal tumorigenesis through Src-mediated activation of the Wnt/β-catenin pathway[J]. Oncotarget, 2015, 6(5): 3123-3135. DOI: 10.18632/oncotarget.3060.
7. Zhao H, Ahirwar DK, Oghumu S, et al. Endothelial Robo4 suppresses breast cancer growth and metastasis through regulation of tumor angiogenesis[J]. Mol Oncol, 2016, 10(2): 272-281. DOI: 10.1016/j.molonc.2015.10.007.
8. Rama N, Dubrac A, Mathivet T, et al. Slit2 signaling through Robo1 and Robo2 is required for retinal neovascularization[J]. Nat Med, 2015, 21(5): 483-491. DOI: 10.1038/nm.3849.
9. Guijarro-Muñoz I, Cuesta AM, Alvarez-Cienfuegos A, et al. The axonal repellent Slit2 inhibits pericyte migration: potential implications in angiogenesis[J]. Exp Cell Res, 2012, 318(4): 371-378. DOI: 10.1016/j.yexcr.2011.12.005.
10. Anand AR, Zhao H, Nagaraja T, et al. N-terminal Slit2 inhibits HIV-1 replication by regulating the actin cytoskeleton[J]. Retrovirology, 2013, 10: 2. DOI: 10.1186/1742-4690-10-2.
11. Fritz RD, Menshykau D, Martin K, et al. SrGAP2-dependent integration of membrane geometry and Slit-Robo-repulsive cues regulates fibroblast contact inhibition of locomotion[J]. Dev Cell, 2015, 35(1): 78-92. DOI: 10.1016/j.devcel.2015.09.002.
12. Enomoto S, Mitsui K, Kawamura T, et al. Suppression of Slit2/Robo1 mediated HUVEC migration by Robo4[J]. Biochem Biophys Res Commun, 2016, 469(4): 797-802. DOI: 10.1016/j.bbrc.2015.12.075.
13. Yang YC, Chen PN, Wang SY, et al. The differential roles of Slit2-exon 15 splicing variants in angiogenesis and HUVEC permeability[J]. Angiogenesis, 2015, 18(3): 301-312. DOI: 10.1007/s10456-015-9467-4.
14. Liu D, Hou J, Hu X, et al. Neuronal chemorepellent Slit2 inhibits vascular smooth muscle cell migration by suppressing small GTPase Rac1 activation[J]. Circ Res, 2006, 98(4): 480-489. DOI: 10.1161/01.RES.0000205764.85931.4b.
15. Ning Y, Sun Q, Dong Y, et al. Slit2-N inhibits PDGF-induced migration in rat airway smooth muscle cells: WASP and Arp2/3 involved[J]. Toxicology, 2011, 283(1): 32-40. DOI: 10.1016/j.tox.2011.01.026.
16. Bartel DP. MicroRNAs: genomics, biogenesis, mechanism, and function[J]. Cell, 2004, 116(2): 281-297.
17. Small EM, Frost RJ, Olson EN. MicroRNAs add a new dimension to cardiovascular disease[J]. Circulation, 2010, 121(8): 1022-1032. DOI: 10.1161/CIRCULATIONAHA.109.889048.
18. Gu JJ, Gao GZ, Zhang SM. miR-218 inhibits the migration and invasion of glioma U87 cells through the Slit2-Robo1 pathway[J]. Oncol Lett, 2015, 9(4): 1561-1566. DOI: 10.3892/ol.2015.2904.
19. Punnamoottil B, Rinkwitz S, Giacomotto J, et al. Motor neuron-expressed microRNAs 218 and their enhancers are nested within introns of Slit2/3 genes[J]. Genesis, 2015, 53 (5): 321-328. DOI: 10.1002/dvg.22852.
20. Tang W, Tang J, He J, et al. SLIT2/ROBO1-miR-218-1-RET/PLAG1: a new disease pathway involved in Hirschsprung’s disease[J]. J Cell Mol Med, 2015, 19(6): 1197-1207. DOI: 10.1111/jcmm.12454.
21. Small EM, Sutherland LB, Rajagopalan KN, et al. MicroRNA-218 regulates vascular patterning by modulation of Slit-Robo signaling[J]. Circ Res, 2010, 107(11): 1336-1344. DOI: 10.1161/CIRCRESAHA.110.227926.
22. Kong Y, Sun B, Han Q, et al. Slit-miR-218-Robo axis regulates retinal neovascularization [J]. Int J Mol Med, 2016, 37(4): 1139-1145.DOI: 10.3892/ijmm.2016.2511.
23. Han S, Kong YC, Sun B, et al. microRNA-218 inhibits oxygen-induced retinal neovascularization via reducing the expression of roundabout 1[J]. Chin Med J (Engl), 2016, 129(6): 709-715. DOI: 10.4103/0366-6999.178013.
24. Yu J, Zhang X, Kuzontkoski PM, et al. Slit2N and Robo4 regulate lymphangiogenesis through the VEGF-C/VEGFR-3 pathway[J]. Cell Commun Signal, 2014, 12: 25. DOI: 10.1186/1478-811X-12-25.
25. Youngblood V, Wang S, Song W, et al. Elevated Slit2 activity impairs VEGF-induced angiogenesis and tumor neovascularization in EphA2-deficient endothelium[J]. Mol Cancer Res, 2015, 13(3): 524-537. DOI: 10.1158/1541-7786.MCR-14-0142.
26. Cai H, Xue Y, Li Z, et al. Roundabout4 suppresses glioma-induced endothelial cell proliferation, migration and tube formation in vitro by inhibiting VEGR2-mediated PI3K/AKT and FAK signaling pathways[J]. Cell Physiol Biochem, 2015, 35(5): 1689-1705. DOI: 10.1159/000373982.
27. Ao JY, Chai ZT, Zhang YY, et al. Robo1 promotes angiogenesis in hepatocellular carcinoma through the Rho family of guanosine triphosphatases' signaling pathway[J]. Tumour Biol, 2015, 36(11): 8413-8424. DOI: 10.1007/s13277-015-3601-1.
28. Wang B, Xiao Y, Ding BB, et al. Induction of tumor angiogenesis by Slit-Robo signaling and inhibition of cancer growth by blocking Robo activity[J]. Cancer Cell, 2003, 4(1): 19-29.
29. Liao WX, Laurent LC, Agent S, et al. Human placental expression of SLIT/ROBO signaling cues: effects of preeclampsia and hypoxia[J]. Biol Reprod, 2012, 86(4): 111. DOI: 10.1095/biolreprod.110.088138.
30. Guo SW, Zheng Y, Lu Y, et al. Slit2 overexpression results in increased microvessel density and lesion size in mice with induced endometriosis[J]. Reprod Sci, 2013, 20(3): 285-298. DOI: 10.1177/1933719112452940.
31. Li P, Peng H, Lu WH, et al. Role of Slit2/Robo1 in trophoblast invasion and vascular remodeling during ectopic tubal pregnancy[J]. Placenta, 2015, 36(10): 1087-1094. DOI: 10.1016/j.placenta.2015.08.002.
32. Han HX, Geng JG. Over-expression of Slit2 induces vessel formation and changes blood vessel permeability in mouse brain[J]. Acta Pharmacol Sin, 2011, 32(11): 1327-1336. DOI: 10.1038/aps.2011.106.
33. Nieminen T, Toivanen PI, Laakkonen JP, et al. Slit2 modifies VEGF-induced angiogenic responses in rabbit skeletal muscle via reduced eNOS activity[J]. Cardiovasc Res, 2015, 107(2): 267-276. DOI: 10.1093/cvr/cvv161.
34. Jones CA, London NR, Chen H, et al. Robo4 stabilizes the vascular network by inhibiting pathologic angiogenesis and endothelial hyperpermeability[J]. Nat Med, 2008, 14(4): 448-453. DOI: 10.1038/nm1742.
35. Li S, Huang L1, Sun Y, et al.Slit2 promotes angiogenic activity via the robo1- VEGFR2- ERK1/2 pathway in both in vivo and in vitro studies[J].Invest Ophthalmol Vis Sci, 2015, 56(9): 5210-5217. DOI: 10.1167/iovs-14-16184.
36. Farnoodian M, Halbach C, Slinger C, et al. High glucose promotes the migration of retinal pigment epithelial cells through increased oxidative stress and PEDF expression[J]. Am J Physiol Cell Physiol, 2016, 311(3): 418-436. DOI: 10.1152/ajpcell.00001.2016.
37. Huang L, Xu Y, Yu W, et al. Effect of Robo1 on retinal pigment epithelial cells and experimental proliferative vitreoretinopathy[J]. Invest Ophthalmol Vis Sci, 2010, 51 (6): 3193-3204. DOI: 10.1167/iovs.09-3779.
38. Zhou W, Yu W, Xie W, et al. The role of SLIT-ROBO signaling in proliferative diabetic retinopathy and retinal pigment epithelial cells[J]. Mol Vis, 2011, 17: 1526-1536.
39. Dubrac A, Genet G, Ola R, et al. Targeting NCK-mediated endothelial cell front-rear polarity inhibits neovascularization[J]. Circulation, 2016, 133(4): 409-421. DOI: 10.1161/CIRCULATIONAHA.115.017537.

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Advanced studies on the role of Slit2-Robo signaling in angiogenesis of fundus oculi and some other organs

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