Robo4 stabilizes the vascular network by inhibiting pathologic angiogenesis and endothelial hyperpermeability
Open accessAbstract
The angiogenic sprout has been compared to the growing axon, and indeed, many proteins direct pathfinding by both structures. The Roundabout (Robo) proteins are guidance receptors with well-established functions in the nervous system; however, their role in the mammalian vasculature remains ill defined. Here we show that an endothelial-specific Robo, Robo4, maintains vascular integrity. Activation of Robo4 by Slit2 inhibits vascular endothelial growth factor (VEGF)-165-induced migration, tube formation and permeability in vitro and VEGF-165-stimulated vascular leak in vivo by blocking Src family kinase activation. In mouse models of retinal and choroidal vascular disease, Slit2 inhibited angiogenesis and vascular leak, whereas deletion of Robo4 enhanced these pathologic processes. Our results define a previously unknown function for Robo receptors in stabilizing the vasculature and suggest that activating Robo4 may have broad therapeutic application in diseases characterized by excessive angiogenesis and/or vascular leak.
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Brain endothelial cells express roundabout guidance receptor 4 (Robo4), which senses slit guidance ligand 2 (Slit2) and maintains blood-retinal barrier integrity by inhibiting VEGF signaling and pathological angiogenesis and endothelial hyperpermeability.
“Brain endothelial cells express roundabout guidance receptor 4 (Robo4), which senses slit guidance ligand 2 (Slit2) and maintains blood-retinal barrier (BRB) integrity by inhibiting VEGF signaling and pathological angiogenesis and endothelial hyperpermeability (297).”
From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [297]
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Cites
Ranibizumab for Neovascular Age-Related Macular Degeneration
Rosenfeld, P. J., Brown, D. M., Heier, J. S., Boyer, D. S., Kaiser, P. K., Chung, C. Y., & Kim, R. Y. (2006) · New England Journal of Medicine · doi:10.1056/nejmoa054481 · Cited by 5,886 · see citing works
Ranibizumab versus Verteporfin for Neovascular Age-Related Macular Degeneration
Brown, D. M., Kaiser, P. K., Michels, M., Soubrane, G., Heier, J. S., Kim, R. Y., Sy, J. P., & Schneider, S. (2006) · New England Journal of Medicine · doi:10.1056/nejmoa062655 · Cited by 3,522 · see citing works
VEGF guides angiogenic sprouting utilizing endothelial tip cell filopodia
Gerhardt, H., Golding, M., Fruttiger, M., Ruhrberg, C., Lundkvist, A., Abramsson, A., Jeltsch, M., Mitchell, C., Alitalo, K., Shima, D., et al. (2003) · The Journal of Cell Biology · doi:10.1083/jcb.200302047 · Cited by 2,894 · see citing works
Self-citationOxygen-induced retinopathy in the mouse.
Smith, L. E. H., Wesolowski, E., McLellan, A., Kostyk, S. K., D’Amato, R. J., Sullivan, R., & D'Amore, P. A. (1994) · PubMed · Cited by 1,627 · see citing works
Common mechanisms of nerve and blood vessel wiring
Carmeliet, P., & Tessier-Lavigne, M. (2005) · Nature · doi:10.1038/nature03875 · Cited by 1,085 · see citing works
Gavard, J., & Gutkind, J. S. (2006) · Nature Cell Biology · doi:10.1038/ncb1486 · Cited by 1,017 · see citing works
Ruhrberg, C., Gerhardt, H., Golding, M., Watson, R., Ioannidou, S., Fujisawa, H., Betsholtz, C., & Shima, D. T. (2002) · Genes & Development · doi:10.1101/gad.242002 · Cited by 918 · see citing works
Self-citationKidd, T., Brose, K., Mitchell, K. J., Fetter, R. D., Tessier‐Lavigne, M., Goodman, C. S., & Tear, G. (1998) · Cell · doi:10.1016/s0092-8674(00)80915-0 · Cited by 882 · see citing works
VEGF-receptor signal transduction
Cross, M. J., Dixelius, J., Matsumoto, T., & Claesson, L. (2003) · Trends in Biochemical Sciences · doi:10.1016/s0968-0004(03)00193-2 · Cited by 864 · see citing works
Selective Requirement for Src Kinases during VEGF-Induced Angiogenesis and Vascular Permeability
Eliceiri, B. P., Paul, R., Schwartzberg, P. L., Hood, J. D., Leng, J., & Cheresh, D. A. (1999) · Molecular Cell · doi:10.1016/s1097-2765(00)80221-x · Cited by 814 · see citing works
Conserved roles for Slit and Robo proteins in midline commissural axon guidance.
Long, H., Sabatier, C., Ma, L., Plump, A., Yuan, W., Ornitz, D., Tamada, A., Murakami, F., Goodman, C., & Tessier-Lavigne, M. (2004) · Neuron · doi:10.1016/s0896-6273(04)00179-5 · Cited by 486 · see citing works
Plump, A. S., Erskine, L., Sabatier, C., Brose, K., Epstein, C. J., Goodman, C. S., Mason, C. A., & Tessier‐Lavigne, M. (2002) · Neuron · doi:10.1016/s0896-6273(01)00586-4 · Cited by 440 · see citing works
Wang, B., Xiao, Y., Ding, B.-B., Zhang, N., Yuan, X., Gui, L., Qian, K.-X., Duan, S., Chen, Z., Rao, Y., et al. (2003) · Cancer Cell · doi:10.1016/s1535-6108(03)00164-8 · Cited by 398 · see citing works
Ozaki, H., Seo, M., Ozaki, K., Yamada, H., Yamada, E., Okamoto, N., Hofmann, F., Wood, J. M., & Campochiaro, P. A. (2000) · American Journal Of Pathology · doi:10.1016/s0002-9440(10)64773-6 · Cited by 346 · see citing works
Eliceiri, B. P., Puente, X. S., Hood, J. D., Stupack, D. G., Schlaepfer, D. D., Huang, X., Sheppard, D., & Cheresh, D. A. (2002) · The Journal of Cell Biology · doi:10.1083/jcb.200109079 · Cited by 333 · see citing works
Robo4 is a vascular-specific receptor that inhibits endothelial migration
Park, K. W., Morrison, C. M., Sorensen, L. K., Jones, C. A., Rao, Y., Chien, C.-B., Wu, J. Y., Urness, L. D., & Li, D. Y. (2003) · Developmental Biology · doi:10.1016/s0012-1606(03)00258-6 · Cited by 324 · see citing works
Self-citationYuan, W., Zhou, L., Chen, J., Wu, J. Y., Rao, Y., & Ornitz, D. M. (1999) · Developmental Biology · doi:10.1006/dbio.1999.9371 · Cited by 299 · see citing works
Sensitive blood-retinal barrier breakdown quantitation using Evans blue.
Xu, Q., Qaum, T., & Adamis, A. P. (2001) · PubMed · Cited by 273 · see citing works
Structural insights into the Slit-Robo complex
Morlot, C., Thielens, N. M., Ravelli, R. B. G., et al. (2007) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0705310104 · Cited by 185 · see citing works
Soluble Robo4 receptor inhibits in vivo angiogenesis and endothelial cell migration
Suchting, S., Heal, P., Tahtis, K., STEWART, L. M. D., & Bicknell, R. (2004) · The FASEB Journal · doi:10.1096/fj.04-1991fje · Cited by 169 · see citing works
Garrett, T. A., van Buul, J. D., & Burridge, K. (2007) · Experimental Cell Research · doi:10.1016/j.yexcr.2007.05.027 · Cited by 164 · see citing works
Binding site for Robo receptors revealed by dissection of the leucine‐rich repeat region of Slit
Howitt, J. A., Clout, N. J., & Hohenester, E. (2004) · The EMBO Journal · doi:10.1038/sj.emboj.7600446 · Cited by 123 · see citing works
Magic roundabout, a tumor endothelial marker: Expression and signaling
Seth, P., Lin, Y., Hanai, J., et al. (2005) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2005.03.250 · Cited by 109 · see citing works
Self-citationAngiogenesis in the mouse retina: A model system for experimental manipulation
Uemura, A., Kusuhara, S., Katsuta, H., et al. (2005) · Experimental Cell Research · doi:10.1016/j.yexcr.2005.10.030 · Cited by 93 · see citing works
Robo4 Signaling in Endothelial Cells Implies Attraction Guidance Mechanisms
Kaur, S., Castellone, M. D., Bedell, V. M., Konar, M., Gutkind, J. S., & Ramchandran, R. (2006) · Journal of Biological Chemistry · doi:10.1074/jbc.m508853200 · Cited by 83 · see citing works
Repellent Signaling by Slit Requires the Leucine-Rich Repeats
Battye, R., Stevens, A., Perry, R. L., et al. (2001) · Journal of Neuroscience · doi:10.1523/jneurosci.21-12-04290.2001 · Cited by 77 · see citing works
Werdich, X. Q., McCollum, G. W., Rajaratnam, V. S., et al. (2004) · Experimental Eye Research · doi:10.1016/j.exer.2004.07.006 · Cited by 67 · see citing works
Slit proteins are not dominant chemorepellents for olfactory tract and spinal motor axons
Patel, K., Nash, J. A. B., Itoh, A., et al. (2001) · Development · doi:10.1242/dev.128.24.5031 · Cited by 47 · see citing works
Suppression and Regression of Choroidal Neovascularization by Polyamine Analogues
Silva, R. L. E., Saishin, Y., Saishin, Y., Akiyama, H., Kachi, S., Aslam, S., Rogers, B. S., Deering, T. G., Gong, Y., Hackett, S. F., et al. (2005) · Investigative Ophthalmology & Visual Science · doi:10.1167/iovs.04-1210 · Cited by 29 · see citing works
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Sorted by citations
Blood-Brain Barrier: From Physiology to Disease and Back
Sweeney, M. D., Zhao, Z., Montagne, A., Nelson, A. R., & Zlokovic, B. V. (2019) · Physiological Reviews · doi:10.1152/physrev.00050.2017 · Cited by 2,294 · see citing works
Tumor angiogenesis: molecular pathways and therapeutic targets
Weis, S. M., & Cheresh, D. A. (2011) · Nature Medicine · doi:10.1038/nm.2537 · Cited by 1,739 · see citing works
miR-126 Regulates Angiogenic Signaling and Vascular Integrity
Fish, J. E., Santoro, M. M., Morton, S. U., Yu, S., Yeh, R.-F., Wythe, J. D., Ivey, K. N., Bruneau, B. G., Stainier, D. Y. R., & Srivastava, D. (2008) · Developmental Cell · doi:10.1016/j.devcel.2008.07.008 · Cited by 1,728 · see citing works
Self-citationMolecular control of endothelial cell behaviour during blood vessel morphogenesis
Herbert, S. P., & Stainier, D. Y. R. (2011) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm3176 · Cited by 1,049 · see citing works
Mazzone, M., Dettori, D., de Oliveira, R. L., Loges, S., Schmidt, T., Jonckx, B., Tian, Y.-M., Lanahan, A. A., Pollard, P. J., de Almodóvar, C. R., et al. (2009) · Cell · doi:10.1016/j.cell.2009.01.020 · Cited by 812 · see citing works
“, 2008), tended to be reduced, while levels of eNOS and Robo4, which promote vessel normalization (Jones et al., 2008; Kashiwagi et al., 2008), were slightly higher in PHD2 ECs (Figure 5A).”
Recent molecular discoveries in angiogenesis and antiangiogenic therapies in cancer
Welti, J. C., Loges, S., Dimmeler, S., & Carmeliet, P. (2013) · Journal of Clinical Investigation · doi:10.1172/jci70212 · Cited by 589 · see citing works
Dynamics of endothelial cell behavior in sprouting angiogenesis
Eilken, H. M., & Adams, R. H. (2010) · Current Opinion in Cell Biology · doi:10.1016/j.ceb.2010.08.010 · Cited by 566 · see citing works
Ephrin-B2 regulates VEGFR2 function in developmental and tumour angiogenesis
Sawamiphak, S., Seidel, S., Essmann, C. L., Wilkinson, G. A., Pitulescu, M. E., Acker, T., & Acker‐Palmer, A. (2010) · Nature · doi:10.1038/nature08995 · Cited by 532 · see citing works
Axon Guidance Molecules in Vascular PatterningPreprint
Adams, R. H., & Eichmann, A. (2010) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a001875 · Cited by 407 · see citing works
“Robo4 expression was preferentially observed in endothelial stalk cells, suggesting that Robo4 could prevent stalk cells from being activated by VEGF (Jones et al. 2008a).”
InfluentialMechanisms of Vessel Branching
Smet, F. D., Segura, I., Bock, K. D., Hohensinner, P. J., & Carmeliet, P. (2009) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/atvbaha.109.185165 · Cited by 398 · see citing works
Coordinating cell behaviour during blood vessel formation
Geudens, I., & Gerhardt, H. (2011) · Development · doi:10.1242/dev.062323 · Cited by 376 · see citing works
“Whereas most studies in the past used histological transverse sections to quantify neo-vessels, recent studies use retinal flat-mounts and FITC-dextran perfusion, vessel labelling or Evans Blue to analyse neo-vessel formation and vascular integrity (Jones et al., 2008; Stahl et al., 2010).”
Self-citationTargeting skeletal endothelium to ameliorate bone loss
Xu, R., Yallowitz, A. R., Qin, A., Wu, Z., Shin, D. Y., Kim, J., Debnath, S., Ji, G., Bostrom, M. P., Yang, X., et al. (2018) · Nature Medicine · doi:10.1038/s41591-018-0020-z · Cited by 376 · see citing works
Endothelial barrier dysfunction in septic shock
Opal, S. M., & van der Poll, T. (2014) · Journal of Internal Medicine · doi:10.1111/joim.12331 · Cited by 351 · see citing works
Targeting Robo4-Dependent Slit Signaling to Survive the Cytokine Storm in Sepsis and Influenza
London, N. R., Zhu, W., Bozza, F. A., Smith, M. C. P., Greif, D. M., Sorensen, L. K., Chen, L., Kaminoh, Y., Chan, A. C., Passi, S. F., et al. (2010) · Science Translational Medicine · doi:10.1126/scitranslmed.3000678 · Cited by 330 · see citing works
“Although two stabilizing regulators of the vascular barrier, Tie2-dependent angiopoietin signaling and Robo4-dependent Slit signaling, use different immediate downstream signaling cascades, both ultimately blunt cytokine-mediated endocytosis of cell surface VE-cadherin (15,16,52).”
InfluentialSelf-citationNovel roles for Slits and netrins: axon guidance cues as anticancer targets?
Mehlen, P., Delloye‐Bourgeois, C., & Chédotal, A. (2011) · Nature reviews. Cancer · doi:10.1038/nrc3005 · Cited by 276 · see citing works
“Different studies have shown that disruption of ROBO4 activity is associated with reduced angiogenesis in vivo”
BackgroundGuidance of Vascular Development
Larrivée, B., Freitas, C., Suchting, S., Brunet, I., & Eichmann, A. (2009) · Circulation Research · doi:10.1161/circresaha.108.188144 · Cited by 266 · see citing works
Regulation of Placental Angiogenesis
Chen, D., & Zheng, J. J. (2013) · Microcirculation · doi:10.1111/micc.12093 · Cited by 243 · see citing works
“Robo4 seems to be a vascular-specific Slit receptor [51,93] that is important for the maintenance of vascular integrity by inhibiting abnormal angiogenesis and endothelial hyperpermeability [55].”
BackgroundFu, J., Gerhardt, H., McDaniel, J. M., Xia, B., Liu, X., Ivanciu, L., Ny, A., Hermans, K., Silasi‐Mansat, R., McGee, S., et al. (2008) · Journal of Clinical Investigation · doi:10.1172/jci36077 · Cited by 242 · see citing works
Self-citationMechanisms of new blood-vessel formation and proliferative heterogeneity of endothelial cells
Naito, H., Iba, T., & Takakura, N. (2020) · International Immunology · doi:10.1093/intimm/dxaa008 · Cited by 241 · see citing works
Renal Endothelial Injury and Microvascular Dysfunction in Acute Kidney Injury
Kumar, S., & Molitoris, B. A. (2015) · Seminars in Nephrology · doi:10.1016/j.semnephrol.2015.01.010 · Cited by 241 · see citing works
“SecinH3 which targets the MYD88-ARNO-ARF6 pathway, has been shown to ameliorate leaky endothelium [100].”
Endothelial permeability and VE-cadherin
Gavard, J. (2014) · Cell Adhesion & Migration · doi:10.4161/cam.29026 · Cited by 233 · see citing works
“Conversely, anti-permeability agents could operate through the blockade of VE-cadherin internalization.(42,62,87) VE-cadherin availability During physiological and pathological blood vessel formation and in response to vascular permeability-promoting agents, the endothelial barrier function could be directly altered t…”
Moving away from the midline: new developments for Slit and Robo
Ypsilanti, A., Zagar, Y., & Chédotal, A. (2010) · Development · doi:10.1242/dev.044511 · Cited by 242 · see citing works
“In zebrafish and mammals, a fourth Robo receptor, Robo4, is expressed by endothelial cells and functions in angiogenesis (Bedell et al., 2005; Jones et al., 2008); this receptor will not be discussed further here.”
BackgroundSlit2–Robo4 signalling promotes vascular stability by blocking Arf6 activity
Jones, C. A., Nishiya, N., London, N. R., Zhu, W., Sorensen, L. K., Chan, A. C., Lim, C. J., Chen, H., Zhang, Q., Schultz, P. G., et al. (2009) · Nature Cell Biology · doi:10.1038/ncb1976 · Cited by 217 · see citing works
Self-citationMolecular Mechanisms of Tumor Angiogenesis
Ziyad, S., & Iruela‐Arispe, M. L. (2011) · Genes & Cancer · doi:10.1177/1947601911432334 · Cited by 218 · see citing works
Branching morphogenesis and antiangiogenesis candidates: tip cells lead the way
Carmeliet, P., Smet, F. D., Loges, S., & Mazzone, M. (2009) · Nature Reviews Clinical Oncology · doi:10.1038/nrclinonc.2009.64 · Cited by 213 · see citing works
“VEGF(R) and angiopoietin-2 inhibitors, endothelial nitric oxide synthase, Robo4 and the RGS5 receptor partially revert this imbalance by promoting 'vessel normalization'”
Robo4 Maintains Vessel Integrity and Inhibits Angiogenesis by Interacting with UNC5B
Koch, A., Mathivet, T., Larrivée, B., Tong, R. K., Kowalski, J., Pibouin-Fragner, L., Bouvrée, K., Stawicki, S. S., Nicholes, K., Rathore, N., et al. (2011) · Developmental Cell · doi:10.1016/j.devcel.2010.12.001 · Cited by 209 · see citing works
“In contrast to these data, another group has reported that Slit-2 functions via Robo4 to inhibit VEGF downstream responses, preventing excessive angiogenesis and permeability (Jones et al., 2008; London et al., 2010; Marlow et al., 2010; Park et al., 2003).”
BackgroundResultInfluentialSlit2 signaling through Robo1 and Robo2 is required for retinal neovascularization
Rama, N., Dubrac, A., Mathivet, T., Chárthaigh, R.-A. N., Genet, G., Cristofaro, B., Pibouin-Fragner, L., Ma, L., Eichmann, A., & Chédotal, A. (2015) · Nature Medicine · doi:10.1038/nm.3849 · Cited by 198 · see citing works
Mechanisms of endothelial cell migration
Michaelis, U. R. (2014) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-014-1678-0 · Cited by 191 · see citing works
Tumor angiogenesis revisited: Regulators and clinical implications
Ronca, R., Benkheil, M., Mitola, S. M. F., Struyf, S., & Liekens, S. (2017) · Medicinal Research Reviews · doi:10.1002/med.21452 · Cited by 193 · see citing works
Disorders of Vascular Permeability
Park‐Windhol, C., & D'Amore, P. A. (2016) · Annual Review of Pathology Mechanisms of Disease · doi:10.1146/annurev-pathol-012615-044506 · Cited by 190 · see citing works
Wiring the Vascular Network with Neural Cues: A CNS Perspective
Wälchli, T., Wacker, A., Frei, K., Regli, L., Schwab, M. E., Hoerstrup, S. P., Gerhardt, H., & Engelhardt, B. (2015) · Neuron · doi:10.1016/j.neuron.2015.06.038 · Cited by 178 · see citing works
Self-citation22q11 Deletion Syndrome: A Role for TBX1 in Pharyngeal and Cardiovascular Development
Scambler, P. J. (2010) · Pediatric Cardiology · doi:10.1007/s00246-009-9613-0 · Cited by 171 · see citing works
Endothelial Progenitor Cells for the Vascularization of Engineered Tissues
Peters, E. B. (2017) · Tissue Engineering Part B Reviews · doi:10.1089/ten.teb.2017.0127 · Cited by 171 · see citing works
“100 ,103,104 The sprouting vessels migrate along the chemoattractant gradient using integrins a v b 3 and a v b 5.”
Mediators of ocular angiogenesis
Qazi, Y., Maddula, S., & Ambati, B. K. (2009) · Journal of Genetics · doi:10.1007/s12041-009-0068-0 · Cited by 173 · see citing works
Signaling Switch of the Axon Guidance Receptor Robo3 during Vertebrate Evolution
Zelina, P., Blockus, H., Zagar, Y., Péres, A., Friocourt, F., Wu, Z., Rama, N., Fouquet, C., Hohenester, E., Tessier‐Lavigne, M., et al. (2014) · Neuron · doi:10.1016/j.neuron.2014.11.004 · Cited by 168 · see citing works
“We also note that Robo4 is now believed to be unable to bind Slits with high affinity, even though initial studies suggested that it did (Jones et al., 2008; Koch et al., 2011).”
Venner, J. M., Hidalgo, L. G., Famulski, K. S., Chang, J. J., & Halloran, P. F. (2015) · American Journal of Transplantation · doi:10.1111/ajt.13115 · Cited by 170 · see citing works
“ROBO4, which is regulated by transcription factor SOX7 (48) (also an ABMRselective transcript), induces VEGF-mediated vessel sprouting (49).”
BackgroundShaping the brain vasculature in development and disease in the single-cell era
Wälchli, T., Bisschop, J., Carmeliet, P., Zadeh, G. M., Monnier, P. P., Bock, K. D., & Radovanovic, I. (2023) · Nature reviews. Neuroscience · doi:10.1038/s41583-023-00684-y · Cited by 163 · see citing works
Repulsive axon guidance molecule Slit3 is a novel angiogenic factor
Zhang, B., Dietrich, U. M., Geng, J.-G., Bicknell, R., Esko, J. D., & Wang, L. (2009) · Blood · doi:10.1182/blood-2008-12-193326 · Cited by 163 · see citing works
MicroRNA-218 Regulates Vascular Patterning by Modulation of Slit-Robo Signaling
Small, E. M., Sutherland, L. B., Rajagopalan, K. N., Wang, S., & Olson, E. N. (2010) · Circulation Research · doi:10.1161/circresaha.110.227926 · Cited by 162 · see citing works
MicroRNAs: Opening a New Vein in Angiogenesis Research
Fish, J. E., & Srivastava, D. (2009) · Science Signaling · doi:10.1126/scisignal.252pe1 · Cited by 160 · see citing works
“Several factors also inhibit angiogenic signaling, including the endothelial cell surface receptor Roundabout homolog 4 (Robo4) (6) and the Notch ligand Delta-like 4 (7), both of which antagonize VEGF signaling.”
ROBO4 variants predispose individuals to bicuspid aortic valve and thoracic aortic aneurysm
Gould, R. A., Aziz, H., Woods, C. E., Seman-Senderos, M. A., Sparks, E. A., Preuß, C., Wünnemann, F., Bedja, D., Moats, C. R., McClymont, S. A., et al. (2018) · Nature Genetics · doi:10.1038/s41588-018-0265-y · Cited by 155 · see citing works
Urbich, C., Rössig, L., Kaluza, D., Potente, M., Boeckel, J., Knau, A., Diehl, F., Geng, J.-G., Hofmann, W., Zeiher, A. M., et al. (2009) · Blood · doi:10.1182/blood-2009-01-196485 · Cited by 153 · see citing works
A Slit/miR-218/Robo regulatory loop is required during heart tube formation in zebrafish
Fish, J. E., Wythe, J. D., Xiao, T., Bruneau, B. G., Stainier, D. Y. R., Srivastava, D., & Woo, S. (2011) · Development · doi:10.1242/dev.060046 · Cited by 150 · see citing works
Self-citationCalmont, A., Ivins, S. M., van Bueren, K. L., et al. (2009) · Development · doi:10.1242/dev.028902 · Cited by 150 · see citing works
Grossmann, A. H., Yoo, J. H., Clancy, J. W., Sorensen, L. K., Sedgwick, A., Tong, Z., Ostanin, K., Rogers, A., Grossmann, K. F., Tripp, S. R., et al. (2013) · Science Signaling · doi:10.1126/scisignal.2003398 · Cited by 150 · see citing works
“For recombinant SLIT2 generation, LOX cells were infected with either empty adenovirus (Mock) or adenovirus containing a SLIT2 expression construct, and either SLIT2 was salt-extracted from the conditioned medium as previously described (62) or the conditioned medium was directly used without salt extraction.”
MethodSelf-citationMutations in 2 distinct genetic pathways result in cerebral cavernous malformations in mice
Chan, A. C., Drakos, S. G., Ruiz, O. E., Smith, A. C. H., Gibson, C. C., Jing, L., Passi, S. F., Stratman, A. N., Sacharidou, A., Revelo, M. P., et al. (2011) · Journal of Clinical Investigation · doi:10.1172/jci44393 · Cited by 145 · see citing works
Self-citationChang, P.-H., Hwang‐Verslues, W. W., Chang, Y., Chen, C.-C., Hsiao, M., Jeng, Y., Chang, K., Lee, E. Y.-H. P., Shew, J., & Lee, W. (2012) · Cancer Research · doi:10.1158/0008-5472.can-12-0877 · Cited by 147 · see citing works
“receptor members been reported to be involved in tumorigenesis (17, 18), we then examined the expressions of Robo1, Robo2, and Robo4 at both mRNA and protein levels among these breast cancer cell lines.”
BackgroundDrakos, S. G., Kfoury, A. G., Hammond, E. H., Reid, B. B., Revelo, M. P., Rasmusson, B. Y., Whitehead, K. J., Salama, M. E., Selzman, C. H., Stehlik, J., et al. (2010) · Journal of the American College of Cardiology · doi:10.1016/j.jacc.2010.04.019 · Cited by 142 · see citing works
Self-citationAxon Guidance Factor SLIT2 Inhibits Neural Invasion and Metastasis in Pancreatic Cancer
Göhrig, A., Detjen, K. M., Hilfenhaus, G., Körner, J. L., Welzel, M., Arsenić, R., Schmuck, R. B., Bahra, M., Wu, J. Y., Wiedenmann, B. J., et al. (2014) · Cancer Research · doi:10.1158/0008-5472.can-13-1012 · Cited by 141 · see citing works
“According to genetic loss-of-function studies, ROBO4 activation via SLIT2 counteracted VEGF-induced vascular leak, whereas disruption of SLIT2–ROBO4 signaling stimulated pathologic angiogenesis and vessel leakiness (45, 46).”
Breaking the VE‐cadherin bonds
Gavard, J. (2008) · FEBS Letters · doi:10.1016/j.febslet.2008.11.032 · Cited by 139 · see citing works
“Similar Src inhibition has been recently demonstrated to oppose to VEGF-induced vascular permeability in response to Robo-4, a ligand for the endothelial Slit-2 receptor [45].”
Zhou, W., Geng, Z. H., Chi, S., et al. (2011) · Cell Research · doi:10.1038/cr.2011.17 · Cited by 136 · see citing works
Robo4 Cooperates with Cxcr4 to Specify Hematopoietic Stem Cell Localization to Bone Marrow Niches
Smith‐Berdan, S., Nguyen, A., Hassanein, D., Zimmer, M., Ugarte, F., Ciriza, J., Li, D., García‐Ojeda, M. E., Hinck, L., & Forsberg, E. C. (2011) · Cell stem cell · doi:10.1016/j.stem.2010.11.030 · Cited by 133 · see citing works
“Robo4 / mice were described previously (Jones et al., 2008; London et al., 2010; Marlow et al., 2010).”
BackgroundInfluentialSelf-citationThe role of actin-binding proteins in the control of endothelial barrier integrity
García‐Ponce, A., Citalán‐Madrid, A. F., Velázquez-Avila, M., Vargas‐Robles, H., & Michael Schnoor, A. (2014) · Thrombosis and Haemostasis · doi:10.1160/th14-04-0298 · Cited by 130 · see citing works
“The endothelial-specific Robo4 has recently been implicated in the regulation of vascular permeability (144, 145).”
Immunomodulatory therapy for severe influenza
Darwish, I., Mubareka, S., & Liles, W. C. (2011) · Expert Review of Anti-infective Therapy · doi:10.1586/eri.11.56 · Cited by 128 · see citing works
The SLIT–ROBO pathway: a regulator of cell function with implications for the reproductive system
Dickinson, R. E., & Duncan, W. C. (2010) · Reproduction · doi:10.1530/rep-10-0017 · Cited by 123 · see citing works
“However, recent research suggests that SLIT2 does indeed bind to the ROBO4 receptor (Jones et al. 2008).”
BackgroundTranscriptional profiling of lung cell populations in idiopathic pulmonary arterial hypertension
Saygın, D., Tabib, T., Bittar, H. E. T., Valenzi, E., Sembrat, J., Chan, S. Y., Rojas, M. M., & Lafyatis, R. (2020) · Pulmonary Circulation · doi:10.1177/2045894020908782 · Cited by 122 · see citing works
Pathogenesis of herpes stromal keratitis – A focus on corneal neovascularization
Giménez, F., Suryawanshi, A. S., & Rouse, B. T. (2012) · Progress in Retinal and Eye Research · doi:10.1016/j.preteyeres.2012.07.002 · Cited by 120 · see citing works
“An additional ways to counteract CV could be to enhance blood vessel endothelial cell signals which negatively regulate VEGF signaling (Jones et al., 2008).”
BackgroundDynamics of angiogenesis in ischemic areas of the infarcted heart
Kobayashi, K., Maeda, K., Takefuji, M., Kikuchi, R., Morishita, Y., Hirashima, M., & Murohara, T. (2017) · Scientific Reports · doi:10.1038/s41598-017-07524-x · Cited by 119 · see citing works
VEGFR signaling during lymphatic vascular development: From progenitor cells to functional vessels
Secker, G. A., & Harvey, N. L. (2014) · Developmental Dynamics · doi:10.1002/dvdy.24227 · Cited by 115 · see citing works
“The Robo4 receptor, together with its ligand Slit2, has been demonstrated to promote stability of the blood vasculature by negatively regulating VEGF signaling (Jones et al., 2008).”
BackgroundEndothelial activation, dysfunction and permeability during severe infections
Lee, W. L., & Liles, W. C. (2011) · Current Opinion in Hematology · doi:10.1097/moh.0b013e328345a3d1 · Cited by 114 · see citing works
MicroRNAs as pharmacological targets in endothelial cell function and dysfunction
Chamorro-Jorganes, A., Araldi, E., & Suárez, Y. (2013) · Pharmacological Research · doi:10.1016/j.phrs.2013.04.002 · Cited by 114 · see citing works
Mechanisms and targets for angiogenic therapy after stroke
Navaratna, D., Guo, S., Arai, K., & Lo, E. H. (2009) · Cell Adhesion & Migration · doi:10.4161/cam.3.2.8396 · Cited by 111 · see citing works
Choroidal Neovascularization: Mechanisms of Endothelial Dysfunction
Yeo, N. J. Y., Chan, E. J. J., & Cheung, C. (2019) · Frontiers in Pharmacology · doi:10.3389/fphar.2019.01363 · Cited by 117 · see citing works
“These laser-treated animal models have since been used to investigate the various molecular mechanisms of choroidal neovascularization and potential pharmacological interventions (Tobe et al., 1998; Bora et al., 2003; Tolentino et al., 2004; Jones et al., 2008).”
BackgroundHorizons in Therapy for Corneal Angiogenesis
Maddula, S., Davis, D. K., Maddula, S., Burrow, M. K., & Ambati, B. K. (2011) · Ophthalmology · doi:10.1016/j.ophtha.2011.01.041 · Cited by 108 · see citing works
Ballard, M. S., & Hinck, L. (2012) · Advances in cancer research · doi:10.1016/b978-0-12-386503-8.00005-3 · Cited by 101 · see citing works
“…in the mature vasculature, thus restraining angiogenesis during pathological neovascular processes (Han and Zhang, 2010; Huang et al., 2009a; Jones et al., 2008, 2009; Koch et al., 2011; London and Li, 2011; Mulik et al., 2011), as well as during normal periods of robust sprouting…”
SLIT/ROBO1 Signaling Suppresses Mammary Branching Morphogenesis by Limiting Basal Cell Number
Macias, H., Moran, A., Samara, Y., Moreno, M. V., Compton, J. E., Harburg, G. C., Strickland, P. A., & Hinck, L. (2011) · Developmental Cell · doi:10.1016/j.devcel.2011.05.012 · Cited by 102 · see citing works
“In contrast, the branching function of SLITs has been chiefly described in the vascular system (Jones et al., 2008; Marlow et al., 2010) and seldom in epithelial organs of vertebrate animals (Grieshammer et al.”
BackgroundCerebral Neovascularization in Diabetes: Implications for Stroke Recovery and beyond
Ergul, A., Abdelsaid, M. A., Fouda, A. Y., & Fagan, S. C. (2014) · Journal of Cerebral Blood Flow & Metabolism · doi:10.1038/jcbfm.2014.18 · Cited by 100 · see citing works
Endophilin-A2 dependent VEGFR2 endocytosis promotes sprouting angiogenesis
Genet, G., Boyé, K., Mathivet, T., Ola, R., Zhang, F., Dubrac, A., Li, J., Genet, N., Geraldo, L. H., Benedetti, L., et al. (2019) · Nature Communications · doi:10.1038/s41467-019-10359-x · Cited by 95 · see citing works
Jiang, Z., Liang, G., Xiao, Y., Qin, T., Chen, X., Wu, E., Ma, Q., & Zheng, W. (2019) · Therapeutic Advances in Medical Oncology · doi:10.1177/1758835919855238 · Cited by 94 · see citing works
Drakos, S. G., Kfoury, A. G., Selzman, C. H., et al. (2011) · Current Opinion in Cardiology · doi:10.1097/hco.0b013e328345af13 · Cited by 94 · see citing works
Self-citationInjury and repair in the neurovascular unit
Xing, C., Hayakawa, K., Lok, J. M., Arai, K., & Lo, E. H. (2012) · Neurological Research · doi:10.1179/1743132812y.0000000019 · Cited by 91 · see citing works
Phuong, T. T. T., Redmon, S. N., Yarishkin, O., Winter, J. M., Li, D. Y., & Križaj, D. (2017) · The Journal of Physiology · doi:10.1113/jp275052 · Cited by 91 · see citing works
“Its sensitivity in studies of BRB breakdown is comparable to radioisotope measurements (Xu et al. 2001; Jones et al. 2008).”
MethodResultSelf-citationZhao, H., Anand, A. R., & Ganju, R. K. (2013) · The Journal of Immunology · doi:10.4049/jimmunol.1302021 · Cited by 90 · see citing works
“The secretory protein Slit2 and its receptors Robo1 and Robo4 are considered to regulate mobility and permeability of endothelial cells and other cell types.”
BackgroundInfluentialJumping the barrier: VE‐cadherin, VEGF and other angiogenic modifiers in cancer
Le Guelte, A., Dwyer, J., & Gavard, J. (2011) · Biology of the Cell · doi:10.1042/bc20110069 · Cited by 91 · see citing works
“…of the mechanism revealed that the Slit2N–Robo4 couplet inhibits VEGF-induced Src activation and phosphorylation of VE-cadherin, which in turn restores and stabilizes the association of VE-cadherin with p120-catenin and therefore prevents from VE-cadherin endocytosis (Jones et al., 2008).”
InfluentialBautch, V. L., & James, J. M. (2009) · Cell Adhesion & Migration · doi:10.4161/cam.3.2.8397 · Cited by 92 · see citing works
Developmental Angiogenesis of the Central Nervous System
Mancuso, M. R., Kuhnert, F., & Kuo, C. J. (2008) · Lymphatic Research and Biology · doi:10.1089/lrb.2008.1014 · Cited by 93 · see citing works
“50 In the postnatal mouse retina, Robo4 is expressed mainly by the endothelial stalk cells of the migrating vascular plexus.”
Vascular endothelial growth factors in cardiovascular medicine
Testa, U., Pannitteri, G., & Condorelli, G. (2008) · Journal of Cardiovascular Medicine · doi:10.2459/jcm.0b013e3283117d37 · Cited by 86 · see citing works
The axonal repellent, Slit2, inhibits directional migration of circulating neutrophils
Tole, S., Mukovozov, I., Huang, Y., et al. (2009) · Journal of Leukocyte Biology · doi:10.1189/jlb.0609391 · Cited by 87 · see citing works
“In vivo, Slit2 inhibits neoangiogenesis by impairing pathologic migration of endothelial cells to vascular endothelial growth factor [18].”
Vascular Robo4 restricts proangiogenic VEGF signaling in breast
Marlow, R., Binnewies, M., Sorensen, L. K., et al. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1001896107 · Cited by 83 · see citing works
“) and coworkers, however, recently showed using the retina as an in vivo model system that loss of Robo4, alone, yielded a phenotype in the adult animal during the process of pathological angiogenesis (13).”
BackgroundMethodResultInfluentialSelf-citationVEGFR2 and Src Kinase Inhibitors Suppress Andes Virus-Induced Endothelial Cell Permeability
Gorbunova, E. E., Gavrilovskaya, I. N., Pepini, T., & Mackow, E. R. (2010) · Journal of Virology · doi:10.1128/jvi.02319-10 · Cited by 82 · see citing works
Binet, F., Mawambo, G., Sitaras, N., Tetreault, N., Lapalme, E., Favret, S., Cerani, A., Leboeuf, D., Tremblay, S., Rezende, F., et al. (2013) · Cell Metabolism · doi:10.1016/j.cmet.2013.02.003 · Cited by 80 · see citing works
“Given the elucidation of key roles for neuronal guidance cues in retinal vascularization (Eichmann and Thomas, 2012; Fukushima et al., 2011; Jones et al., 2008; Joyal et al., Ce 2011; Kim et al., 2011; Larrivée et al., 2007), we turned our attention to these molecules.”
BackgroundOxygen-Dependent Cleavage of the p75 Neurotrophin Receptor Triggers Stabilization of HIF-1α
Moan, N. L., Houslay, D. M., Frank, C., Houslay, M. D., & Akassoglou, K. (2011) · Molecular Cell · doi:10.1016/j.molcel.2011.08.033 · Cited by 80 · see citing works
“…used in vivo to examine the biological role of HIF-1a (Xia et al., 2008; Yoshida et al., 2010) and is an establishedmodel to validate new regulators of hypoxia-induced pathological neoangiogenesis, such as JNK (Guma et al., 2009), Notch (Hellström et al., 2007), and Robo4 (Jones et al., 2008).”
Endothelial permeability and VE-cadherin
Gavard, J. (2013) · Cell Adhesion & Migration · doi:10.4161/cam.27330 · Cited by 77 · see citing works
Fritz, R. D., Menshykau, D., Martin, K., Reimann, A., Pontelli, V., & Pertz, O. C. (2015) · Developmental Cell · doi:10.1016/j.devcel.2015.09.002 · Cited by 76 · see citing works
Benedito, R., Trindade, A., Hirashima, M., Henrique, D., Lopes-da-Costa, L., Rossant, J., Gill, P. S., & Duarte, A. (2008) · BMC Developmental Biology · doi:10.1186/1471-213x-8-117 · Cited by 74 · see citing works
Di, M., Wang, L., Li, M., Zhang, Y., Liu, X., Zeng, R., Wang, H., Chen, Y., Chen, W., Zhang, Y., et al. (2017) · Cell Death and Disease · doi:10.1038/cddis.2017.277 · Cited by 74 · see citing works
The Endometrium in Adenomyosis
Benagiano, G., & Brosens, I. A. (2012) · Women s Health · doi:10.2217/whe.12.8 · Cited by 73 · see citing works
Tung, J., Chiaretti, S., Dean, M. M., Sultana, A. J., Reade, M. C., & Fung, Y. L. (2022) · Blood Reviews · doi:10.1016/j.blre.2021.100926 · Cited by 73 · see citing works
Heparan sulfate in angiogenesis: a target for therapy
van Wijk, X. M. R., & Kuppevelt, T. H. V. (2013) · Angiogenesis · doi:10.1007/s10456-013-9401-6 · Cited by 70 · see citing works
MicroRNA Control of Vascular Endothelial Growth Factor Signaling Output During Vascular Development
Dang, L. T. H., Lawson, N. D., & Fish, J. E. (2013) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/atvbaha.112.300142 · Cited by 70 · see citing works
Paul, J., Coulombe, K. L. K., Tóth, P. T., Zhang, Y., Marsboom, G., Bindokas, V. P., Smith, D. W., Murry, C. E., & Rehman, J. (2013) · Journal of Molecular and Cellular Cardiology · doi:10.1016/j.yjmcc.2013.09.005 · Cited by 70 · see citing works
“However, when SLIT2 is bound to ROBO4 in normal vascular homeostasis, this is a stabilizing signal for the vasculature to inhibit VEGF-induced EC migration, tube formation, and permeability in vitro and prevent pathologic angiogenesis in the eye [26].”
Angiogenesis in melanoma: an update with a focus on current targeted therapies
Jour, G., Ivan, D. S., & Aung, P. P. (2016) · Journal of Clinical Pathology · doi:10.1136/jclinpath-2015-203482 · Cited by 68 · see citing works
The neurovascular link in health and disease: an update
Segura, I., Smet, F. D., Hohensinner, P. J., de Almodóvar, C. R., & Carmeliet, P. (2009) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2009.08.005 · Cited by 68 · see citing works
Zhang, B., Xiao, W., Qiu, H. Y., Zhang, F., Moniz, H. A., Jaworski, A., Condac, E., Gutiérrez‐Sánchez, G., Heiß, C., Clugston, R. D., et al. (2013) · Journal of Clinical Investigation · doi:10.1172/jci71090 · Cited by 68 · see citing works
“The diaphragm was isolated, fixed in 2% PFA and 0.2% glutaraldehyde in PBS, and then stained with X-gal solution overnight at 37°C. AP activity in Robo4 +/– mice was detected as previously described (18).”
InfluentialSelf-citationFranck, G., Dai, J., Fifre, A., Ngo, S., Hur, J. C., Michineau, S., Allaire, É., & Gervais, M. (2013) · Circulation · doi:10.1161/circulationaha.113.001677 · Cited by 67 · see citing works
Understanding the Mechanisms of Callosal Development Through the Use of Transgenic Mouse Models
Donahoo, A.-L. S., & Richards, L. J. (2009) · Seminars in Pediatric Neurology · doi:10.1016/j.spen.2009.07.003 · Cited by 67 · see citing works
Common Factors Regulating Patterning of the Nervous and Vascular Systems*
Melani, M., & Weinstein, B. M. (2010) · Annual Review of Cell and Developmental Biology · doi:10.1146/annurev.cellbio.093008.093324 · Cited by 65 · see citing works
“Mice were generated with the Robo4 allele replaced by an alkaline phosphatase (AP) gene (robo4AP) ( C.A. Jones et al. 2008).”
BackgroundMethodDarwish, I., & Liles, W. C. (2013) · Virulence · doi:10.4161/viru.25740 · Cited by 63 · see citing works
Endogenous endothelial cell signaling systems maintain vascular stability
London, N. R., Whitehead, K. J., & Li, D. Y. (2009) · Angiogenesis · doi:10.1007/s10456-009-9130-z · Cited by 63 · see citing works
Self-citationThe complex link between influenza and severe sepsis
Florescu, D. F., & Kalil, A. C. (2013) · Virulence · doi:10.4161/viru.27103 · Cited by 61 · see citing works
“The counter-regulator of the cytokine-mediated endocytosis of VE-cadherins and stabilizer of the vascular barrier is the Robo4-dependent Slit signaling mechanism.(31,32) London et al.”
Background
- Authors
- Jones, C. A., London, N. R., Chen, H., Park, K. W., Sauvaget, D., Stockton, R. A., Wythe, J. D., Suh, W., Larrieu-Lahargue, F., Mukouyama, Y.-S., Lindblom, P., Seth, P., Frias, A., Nishiya, N., Ginsberg, M. H., Gerhardt, H., Zhang, K., & Li, D. Y.
- Affiliations
- University of Utah (US)
- Cancer Research UK (GB)
- University of California San Diego (US)
- National Institutes of Health (US)
- Beth Israel Deaconess Medical Center (US)
- Corresponding author
- Zhang, Kang
- Li, Dean Y
- ORCID
- Venue
- Nature Medicine
- Published
- 2008-03-16
- Volume
- 14
- Issue
- 4
- Pages
- 448-453
- ISSN
- 1078-8956 (ISSN-L)
- 1546-170X
- PMC
- PMC2875252
- OpenAlex
- W2010486643
- Semantic Scholar
- ce41d0b27996f4149ab37e8d9e9d23274c3afdee
- Cited by
- 392
- References
- 29
- Citations by year
- 2026: 11 · 2025: 10 · 2024: 11 · 2023: 9 · 2022: 16 · 2021: 15 · 2020: 20 · 2019: 22 · 2018: 16 · 2017: 24 · 2016: 18 · 2015: 29 · 2014: 29 · 2013: 38 · 2012: 25
- FWCI
- 13.56
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature Medicine (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- MDC Repository (Max-Delbrueck-Center for Molecular Medicine) (submittedVersion)
- Funders
- Cancer Research UK
- National Institutes of Health (4r01hl084516-08)
- National Heart, Lung, and Blood Institute (R01HL065648, Z01HL005702, R01HL-084516, R01HL077671, R01HL068873)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Angiogenesis and VEGF in Cancer
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Axon Guidance and Neuronal Signaling
- Health Sciences › Medicine › Oncology › Lymphatic System and Diseases
- Keywords
- Robo4, Slit2, pathological angiogenesis, vascular leakage, endothelial hyperpermeability, VEGF165, Src family kinases, retinal vascular disease, choroidal vascular disease, vascular integrity, endothelial cell migration, tube formation
- MeSH terms
- Roundabout Proteins, Slit Homolog 2 Protein, Animals, Capillary Permeability, Choroid, Endothelium, Vascular, Humans, Mice, Transgenic, Neovascularization, Pathologic, Nerve Tissue Proteins, Receptors, Immunologic, Recombinant Proteins, Retinal Vessels, Signal Transduction, Mice, Knockout, Intercellular Signaling Peptides and Proteins, Vascular Endothelial Growth Factor A, Mice
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