Abstract
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 first identified 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.
Keywords: netrin-1, angiogenesis, cerebral ischemia, neuronal recovery
References
- [1].Go AS, Mozaffarian D, Roger VL, Benjamin EJ, Berry JD, Borden WB, et al. Heart disease and stroke statistics—2013 update: a report from the American Heart Association. Circulation. 2013;127:e6–e245. doi: 10.1161/CIR.0b013e31828124ad. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [2].Hacke W, Kaste M, Bluhmki E, Brozman M, Davalos A, Guidetti D, et al. Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke. N Engl J Med. 2008;359:1317–1329. doi: 10.1056/NEJMoa0804656. [DOI] [PubMed] [Google Scholar]
- [3].Liu Y, Stein E, Oliver T, Li Y, Brunken WJ, Koch M, et al. Novel role for Netrins in regulating epithelial behavior during lung branching morphogenesis. Curr Biol. 2004;14:897–905. doi: 10.1016/j.cub.2004.05.020. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [4].De Breuck S, Lardon J, Rooman I, Bouwens L. Netrin-1 expression in fetal and regenerating rat pancreas and its effect on the migration of human pancreatic duct and porcine islet precursor cells. Diabetologia. 2003;46:926–933. doi: 10.1007/s00125-003-1125-5. [DOI] [PubMed] [Google Scholar]
- [5].Strizzi L, Mancino M, Bianco C, Raafat A, Gonzales M, Booth BW, et al. Netrin-1 can affect morphogenesis and differentiation of the mouse mammary gland. J Cell Physiol. 2008;216:824–834. doi: 10.1002/jcp.21462. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [6].Salminen M, Meyer BI, Bober E, Gruss P. Netrin 1 is required for semicircular canal formation in the mouse inner ear. Development. 2000;127:13–22. doi: 10.1242/dev.127.1.13. [DOI] [PubMed] [Google Scholar]
- [7].Mehlen P, Guenebeaud C. Netrin-1 and its dependence receptors as original targets for cancer therapy. Curr Opin Oncol. 2010;22:46–54. doi: 10.1097/CCO.0b013e328333dcd1. [DOI] [PubMed] [Google Scholar]
- [8].Ly NP, Komatsuzaki K, Fraser IP, Tseng AA, Prodhan P, Moore KJ, et al. Netrin-1 inhibits leukocyte migration in vitro and in vivo. Proc Natl Acad Sci U S A. 2005;102:14729–14734. doi: 10.1073/pnas.0506233102. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [9].Ranganathan PV, Jayakumar C, Mohamed R, Dong Z, Ramesh G. Netrin-1 regulates the inflammatory response of neutrophils and macrophages, and suppresses ischemic acute kidney injury by inhibiting COX-2-mediated PGE2 production. Kidney Int. 2013;83:1087–1098. doi: 10.1038/ki.2012.423. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [10].Son TW, Yun SP, Yong MS, Seo BN, Ryu JM, Youn HY, et al. Netrin-1 protects hypoxia-induced mitochondrial apoptosis through HSP27 expression via DCC- and integrin alpha6beta4-dependent Akt, GSK-3beta, and HSF-1 in mesenchymal stem cells. Cell Death Dis. 2013;4:e563. doi: 10.1038/cddis.2013.94. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [11].Reeves WB, Kwon O, Ramesh G. Netrin-1 and kidney injury. II. Netrin-1 is an early biomarker of acute kidney injury. Am J Physiol Renal Physiol. 2008;294:F731–738. doi: 10.1152/ajprenal.00507.2007. [DOI] [PubMed] [Google Scholar]
- [12].Ramesh G, Berg A, Jayakumar C. Plasma netrin-1 is a diagnostic biomarker of human cancers. Biomarkers. 2011;16:172–180. doi: 10.3109/1354750X.2010.541564. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [13].Bayat M, Baluchnejadmojarad T, Roghani M, Goshadrou F, Ronaghi A, Mehdizadeh M. Netrin-1 improves spatial memory and synaptic plasticity impairment following global ischemia in the rat. Brain Res. 2012;1452:185–194. doi: 10.1016/j.brainres.2012.03.008. [DOI] [PubMed] [Google Scholar]
- [14].Wu TW, Li WW, Li H. Netrin-1 attenuates ischemic strokeinduced apoptosis. Neuroscience. 2008;156:475–482. doi: 10.1016/j.neuroscience.2008.08.015. [DOI] [PubMed] [Google Scholar]
- [15].Lu H, Wang Y, Yuan F, Liu J, Zeng L, Yang GY. Overexpression of netrin-1 improves neurological outcomes in mice following transient middle cerebral artery occlusion. Front Med. 2011;5:86–93. doi: 10.1007/s11684-011-0118-x. [DOI] [PubMed] [Google Scholar]
- [16].Liao SJ, Gong Q, Chen XR, Ye LX, Ding Q, Zeng JS, et al. Netrin-1 rescues neuron loss by attenuating secondary apoptosis in ipsilateral thalamic nucleus following focal cerebral infarction in hypertensive rats. Neuroscience. 2013;231:225–232. doi: 10.1016/j.neuroscience.2012.11.059. [DOI] [PubMed] [Google Scholar]
- [17].Cirulli V, Yebra M. Netrins: beyond the brain. Nat Rev Mol Cell Biol. 2007;8:296–306. doi: 10.1038/nrm2142. [DOI] [PubMed] [Google Scholar]
- [18].Bradford D, Cole SJ, Cooper HM. Netrin-1: diversity in development. Int J Biochem Cell Biol. 2009;41:487–493. doi: 10.1016/j.biocel.2008.03.014. [DOI] [PubMed] [Google Scholar]
- [19].Rajasekharan S, Kennedy TE. The netrin protein family. Genome Biol. 2009;10:239. doi: 10.1186/gb-2009-10-9-239. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [20].Lai Wing Sun K, Correia JP, Kennedy TE. Netrins: versatile extracellular cues with diverse functions. Development. 2011;138:2153–2169. doi: 10.1242/dev.044529. [DOI] [PubMed] [Google Scholar]
- [21].Eichmann A, Makinen T, Alitalo K. Neural guidance molecules regulate vascular remodeling and vessel navigation. Genes Dev. 2005;19:1013–1021. doi: 10.1101/gad.1305405. [DOI] [PubMed] [Google Scholar]
- [22].Engelkamp D. Cloning of three mouse Unc5 genes and their expression patterns at mid-gestation. Mech Dev. 2002;118:191–197. doi: 10.1016/S0925-4773(02)00248-4. [DOI] [PubMed] [Google Scholar]
- [23].Yang B, Peng G, Gao J. Expression of unc5 family genes in zebrafish brain during embryonic development. Gene Expr Patterns. 2013;13:311–318. doi: 10.1016/j.gep.2013.06.001. [DOI] [PubMed] [Google Scholar]
- [24].Dakouane-Giudicelli M, Duboucher C, Fortemps J, Missey-Kolb H, Brule D, Giudicelli Y, et al. Characterization and expression of netrin-1 and its receptors UNC5B and DCC in human placenta. J Histochem Cytochem. 2010;58:73–82. doi: 10.1369/jhc.2009.953463. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [25].Castets M, Coissieux MM, Delloye-Bourgeois C, Bernard L, Delcros JG, Bernet A, et al. Inhibition of endothelial cell apoptosis by netrin-1 during angiogenesis. Dev Cell. 2009;16:614–620. doi: 10.1016/j.devcel.2009.02.006. [DOI] [PubMed] [Google Scholar]
- [26].Navankasattusas S, Whitehead KJ, Suli A, Sorensen LK, Lim AH, Zhao J, et al. The netrin receptor UNC5B promotes angiogenesis in specific vascular beds. Development. 2008;135:659–667. doi: 10.1242/dev.013623. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [27].Lu X, Le Noble F, Yuan L, Jiang Q, De Lafarge B, Sugiyama D, et al. The netrin receptor UNC5B mediates guidance events controlling morphogenesis of the vascular system. Nature. 2004;432:179–186. doi: 10.1038/nature03080. [DOI] [PubMed] [Google Scholar]
- [28].Larrivee B, Freitas C, Trombe M, Lv X, Delafarge B, Yuan L, et al. Activation of the UNC5B receptor by Netrin-1 inhibits sprouting angiogenesis. Genes Dev. 2007;21:2433–2447. doi: 10.1101/gad.437807. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [29].Corset V, Nguyen-Ba-Charvet KT, Forcet C, Moyse E, Chedotal A, Mehlen P. Netrin-1-mediated axon outgrowth and cAMP production requires interaction with adenosine A2b receptor. Nature. 2000;407:747–750. doi: 10.1038/35037600. [DOI] [PubMed] [Google Scholar]
- [30].Stein E, Zou Y, Poo M, Tessier-Lavigne M. Binding of DCC by netrin-1 to mediate axon guidance independent of adenosine A2B receptor activation. Science. 2001;291:1976–1982. doi: 10.1126/science.1059391. [DOI] [PubMed] [Google Scholar]
- [31].McKenna WL, Wong-Staal C, Kim GC, Macias H, Hinck L, Bartoe JL. Netrin-1-independent adenosine A2b receptor activation regulates the response of axons to netrin-1 by controlling cell surface levels of UNC5A receptors. J Neurochem. 2008;104:1081–1090. doi: 10.1111/j.1471-4159.2007.05040.x. [DOI] [PubMed] [Google Scholar]
- [32].Yebra M, Montgomery AM, Diaferia GR, Kaido T, Silletti S, Perez B, et al. Recognition of the neural chemoattractant Netrin-1 by integrins alpha6beta4 and alpha3beta1 regulates epithelial cell adhesion and migration. Dev Cell. 2003;5:695–707. doi: 10.1016/S1534-5807(03)00330-7. [DOI] [PubMed] [Google Scholar]
- [33].Ishii N, Wadsworth WG, Stern BD, Culotti JG, Hedgecock EM. UNC-6, a laminin-related protein, guides cell and pioneer axon migrations in C. elegans. Neuron. 1992;9:873–881. doi: 10.1016/0896-6273(92)90240-E. [DOI] [PubMed] [Google Scholar]
- [34].Serafini T, Kennedy TE, Galko MJ, Mirzayan C, Jessell T T-L M. The netrins define a family of axon outgrowth-promoting proteins homologous to C. elegans UNC-6. Cell. 1994;78:409–424. doi: 10.1016/0092-8674(94)90420-0. [DOI] [PubMed] [Google Scholar]
- [35].Moon C, Ahn M, Jeong C, Kim H, Shin T. Immunohistochemical study of netrin-1 in the spinal cord with rat experimental autoimmune encephalomyelitis. Immunol Invest. 2011;40:160–171. doi: 10.3109/08820139.2010.525570. [DOI] [PubMed] [Google Scholar]
- [36].Livesey FJ, Hunt SP. Netrin and netrin receptor expression in the embryonic mammalian nervous system suggests roles in retinal, striatal, nigral, and cerebellar development. Mol Cell Neurosci. 1997;8:417–429. doi: 10.1006/mcne.1997.0598. [DOI] [PubMed] [Google Scholar]
- [37].Shatzmiller RA, Goldman JS, Simard-Emond L, Rymar V, Manitt C, Sadikot AF, et al. Graded expression of netrin-1 by specific neuronal subtypes in the adult mammalian striatum. Neuroscience. 2008;157:621–636. doi: 10.1016/j.neuroscience.2008.09.031. [DOI] [PubMed] [Google Scholar]
- [38].Dalvin S, Anselmo MA, Prodhan P, Komatsuzaki K, Schnitzer JJ, Kinane TB. Expression of Netrin-1 and its two receptors DCC and UNC5H2 in the developing mouse lung. Gene Expr Patterns. 2003;3:279–283. doi: 10.1016/S1567-133X(03)00047-4. [DOI] [PubMed] [Google Scholar]
- [39].Chen J, Cai QP, Shen PJ, Yan RL, Wang CM, Yang DJ, et al. Netrin-1 protects against L-Arginine-induced acute pancreatitis in mice. PLoS One. 2012;7:e46201. doi: 10.1371/journal.pone.0046201. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [40].Srinivasan K, Strickland P, Valdes A, Shin GC, Hinck L. Netrin-1/neogenin interaction stabilizes multipotent progenitor cap cells during mammary gland morphogenesis. Dev Cell. 2003;4:371–382. doi: 10.1016/S1534-5807(03)00054-6. [DOI] [PubMed] [Google Scholar]
- [41].Llambi F, Causeret F, Bloch-Gallego E, Mehlen P. Netrin-1 acts as a survival factor via its receptors UNC5H and DCC. EMBO J. 2001;20:2715–2722. doi: 10.1093/emboj/20.11.2715. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [42].Mei F, Christin Chong SY, Chan JR. Myelin-based inhibitors of oligodendrocyte myelination: clues from axonal growth and regeneration. Neurosci Bull. 2013;29:177–188. doi: 10.1007/s12264-013-1319-x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [43].Serafini T, Colamarino SA, Leonardo ED, Wang H, Beddington R, Skarnes WC, et al. Netrin-1 is required for commissural axon guidance in the developing vertebrate nervous system. Cell. 1996;87:1001–1014. doi: 10.1016/S0092-8674(00)81795-X. [DOI] [PubMed] [Google Scholar]
- [44].Larrivee B, Freitas C, Suchting S, Brunet I, Eichmann A. Guidance of vascular development: lessons from the nervous system. Circ Res. 2009;104:428–441. doi: 10.1161/CIRCRESAHA.108.188144. [DOI] [PubMed] [Google Scholar]
- [45].Carmeliet P, Tessier-Lavigne M. Comm on mechanisms of nerve and blood vessel wiring. Nature. 2005;436:193–200. doi: 10.1038/nature03875. [DOI] [PubMed] [Google Scholar]
- [46].Dickson BJ. Molecular mechanisms of a xon guidance. Science. 2002;298:1959–1964. doi: 10.1126/science.1072165. [DOI] [PubMed] [Google Scholar]
- [47].Klagsbrun M, Eichmann A. A role for ax on guidance receptors and ligands in blood vessel development and tumor angiogenesis. Cytokine Growth Factor Rev. 2005;16:535–548. doi: 10.1016/j.cytogfr.2005.05.002. [DOI] [PubMed] [Google Scholar]
- [48].Semenza GL. Vasculogenesis, angiogenesis, and arteriogenesis: mechanisms of blood vessel formation and remodeling. J Cell Biochem. 2007;102:840–847. doi: 10.1002/jcb.21523. [DOI] [PubMed] [Google Scholar]
- [49].Potente M, Gerhardt H, Carmeliet P. Basi c and therapeutic aspects of angiogenesis. Cell. 2011;146:873–887. doi: 10.1016/j.cell.2011.08.039. [DOI] [PubMed] [Google Scholar]
- [50].Chavakis E, Dimmeler S. Regulation of end othelial cell survival and apoptosis during angiogenesis. Arterioscler Thromb Vasc Biol. 2002;22:887–893. doi: 10.1161/01.ATV.0000017728.55907.A9. [DOI] [PubMed] [Google Scholar]
- [51].Carmeliet P, Jain RK. Molecular mechanisms and clinical applications of angiogenesis. Nature. 2011;473:298–307. doi: 10.1038/nature10144. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [52].Park KW, Crouse D, Lee M, Karnik SK, Sorensen LK, Murphy KJ, et al. The axonal attractant Netrin-1 is an angiogenic factor. Proc Natl Acad Sci U S A. 2004;101:16210–16215. doi: 10.1073/pnas.0405984101. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [53].Wilson BD, Ii M, Park KW, Suli A, Sorensen L K, Larrieu-Lahargue F, et al. Netrins promote developmental and therapeutic angiogenesis. Science. 2006;313:640–644. doi: 10.1126/science.1124704. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [54].Fan Y, Shen F, Chen Y, Hao Q, Liu W, Su H, et al. Overexpression of netrin-1 induces neovascularization in the adult mouse brain. J Cereb Blood Flow Metab. 2008;28:1543–1551. doi: 10.1038/jcbfm.2008.39. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [55].Nguyen A, Cai H. Netrin-1 induces angiogenesis via a DCCdependent ERK1/2-eNOS feed-forward mechanism. Proc Natl Acad Sci U S A. 2006;103:6530–6535. doi: 10.1073/pnas.0511011103. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [56].Yang Y, Zou L, Wang Y, Xu KS, Zhang JX, Zhang J H. Axon guidance cue Netrin-1 has dual function in angiogenesis. Cancer Biol Ther. 2007;6:743–748. doi: 10.4161/cbt.6.5.3976. [DOI] [PubMed] [Google Scholar]
- [57].Krupinski J, Kaluza J, Kumar P, Kumar S, Wang JM. Role of angiogenesis in patients with cerebral ischemic stroke. Stroke. 1994;25:1794–1798. doi: 10.1161/01.STR.25.9.1794. [DOI] [PubMed] [Google Scholar]
- [58].Sbarbati A, Pietra C, Baldassarri AM, Guerrini U, Ziviani L, Reggiani A, et al. The microvascular system in ischemic cortical lesions. Acta Neuropathol. 1996;92:56–63. doi: 10.1007/s004010050489. [DOI] [PubMed] [Google Scholar]
- [59].Hayashi T, Noshita N, Sugawara T, Chan PH. Temporal profile of angiogenesis and expression of related genes in the brain after ischemia. J Cereb Blood Flow Metab. 2003;23:166–180. doi: 10.1097/00004647-200302000-00004. [DOI] [PubMed] [Google Scholar]
- [60].Beck H, Acker T, Wiessner C, Allegrini PR, Plate KH. Expression of angiopoietin-1, angiopoietin-2, and tie receptors after middle cerebral artery occlusion in the rat. Am J Pathol. 2000;157:1473–1483. doi: 10.1016/S0002-9440(10)64786-4. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [61].Tian HL, Chen H, Cui YH, Xu T, Zhou LF. Increased protein and mRNA expression of endostatin in the ischemic brain tissue of rabbits after middle cerebral artery occlusion. Neurosci Bull. 2007;23:35–40. doi: 10.1007/s12264-007-0005-2. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [62].Seevinck PR, Deddens LH, Dijkhuizen RM. Magnetic resonance imaging of brain angiogenesis after stroke. Angiogenesis. 2010;13:101–111. doi: 10.1007/s10456-010-9174-0. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [63].Yu SW, Friedman B, Cheng Q, Lyden PD. Stroke-evoked angiogenesis results in a transient population of microvessels. J Cereb Blood Flow Metab. 2007;27:755–763. doi: 10.1038/sj.jcbfm.9600378. [DOI] [PubMed] [Google Scholar]
- [64].Wei L, Erinjeri JP, Rovainen CM, Woolsey TA. Collateral growth and angiogenesis around cortical stroke. Stroke. 2001;32:2179–2184. doi: 10.1161/hs0901.094282. [DOI] [PubMed] [Google Scholar]
- [65].Le Magueresse C, Alfonso J, Bark C, Eliava M, Khrulev S, Monyer H. Subventricular zone-derived neuroblasts use vasculature as a scaffold to migrate radially to the cortex in neonatal mice. Cereb Cortex. 2012;22:2285–2296. doi: 10.1093/cercor/bhr302. [DOI] [PubMed] [Google Scholar]
- [66].Thored P, Wood J, Arvidsson A, Cammenga J, Kokaia Z, Lindvall O. Long-term neuroblast migration along blood vessels in an area with transient angiogenesis and increased vascularization after stroke. Stroke. 2007;38:3032–3039. doi: 10.1161/STROKEAHA.107.488445. [DOI] [PubMed] [Google Scholar]
- [67].Kojima T, Hirota Y, Ema M, Takahashi S, Miyoshi I, Okano H, et al. Subventricular zone-derived neural progenitor cells migrate along a blood vessel scaffold toward the post-stroke striatum. Stem Cells. 2010;28:545–554. doi: 10.1002/stem.306. [DOI] [PubMed] [Google Scholar]
- [68].Xiong Y, Mahmood A, Chopp M. Angiogenesis, neurogenesis and brain recovery of function following injury. Curr Opin Investig Drugs. 2010;11:298–308. [PMC free article] [PubMed] [Google Scholar]
- [69].Liman TG, Endres M. New vessels after stroke: postischemic neovascularization and regeneration. Cerebrovasc Dis. 2012;33:492–499. doi: 10.1159/000337155. [DOI] [PubMed] [Google Scholar]
- [70].Liu N, Huang H, Lin F, Chen A, Zhang Y, Chen R, et al. Effects of treadmill exercise on the expression of netrin-1 and its receptors in rat brain after cerebral ischemia. Neuroscience. 2011;194:349–358. doi: 10.1016/j.neuroscience.2011.07.037. [DOI] [PubMed] [Google Scholar]
- [71].Tsuchiya A, Hayashi T, Deguchi K, Sehara Y, Yamashita T, Zhang H, et al. Expression of netrin-1 and its receptors DCC and neogenin in rat brain after ischemia. Brain Res. 2007;1159:1–7. doi: 10.1016/j.brainres.2006.12.096. [DOI] [PubMed] [Google Scholar]
- [72].Eichmann A, Thomas JL. Molecular parallels between neural and vascular development. Cold Spring Harb Perspect Med. 2013;3:a006551. doi: 10.1101/cshperspect.a006551. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [73].Sun H, Le T, Chang TT, Habib A, Wu S, Shen F, et al. AAV-mediated netrin-1 overexpression increases peri-infarct blood vessel density and improves motor function recovery after experimental stroke. Neurobiol Dis. 2011;44:73–83. doi: 10.1016/j.nbd.2011.06.006. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [74].Lu H, Wang Y, He X, Yuan F, Lin X, Xie B, et al. Netrin-1 hypere xpression in mouse brain promotes angiogenesis and long-term neurological recovery after transient focal ischemia. Stroke. 2012;43:838–843. doi: 10.1161/STROKEAHA.111.635235. [DOI] [PubMed] [Google Scholar]