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Table of Contents
Vol. 14, No. 5, 2005
Issue release date: November 2005
Section title: Review
Neurosignals 2005;14:207–221

Neuroprotective Role of Vascular Endothelial Growth Factor: Signalling Mechanisms, Biological Function, and Therapeutic Potential

Zachary I.
Centre for Cardiovascular Biology and Medicine, BHF Laboratories, Department of Medicine, The Rayne Institute, University College London, London, UK
email Corresponding Author

Ian Zachary

Centre for Cardiovascular Biology and Medicine, BHF Laboratories

Department of Medicine, The Rayne Institute, University College London

5 University Street, London WC1E 6JJ (UK)

Tel. +44 20 7679 6620, Fax +44 20 7679 6212, E-Mail I.Zachary@ucl.ac.uk


  1. Senger DR, Galli SJ, Dvorak AM, Perruzzi CA, Harvey VS, Dvorak HF: Tumor cells secrete a vascular permeability factor that promotes accumulation of ascites fluid. Science 1983;219:983–985.
  2. Leung DW, Cachianes G, Kuang WJ, Goeddel DV, Ferrara N: Vascular endothelial growth factor is a secreted angiogenic mitogen. Science 1989;246:1306–1309.
  3. Keck PJ, Hauser SD, Krivi G, Sanzo K, Warren T, Feder J, Connolly DT: Vascular permeability factor, an endothelial cell mitogen related to PDGF. Science 1989;246:1309–1312.
  4. Ferrara N, Gerber HP, LeCouter J: The biology of VEGF and its receptors. Nat Med 2003;9:669–676.
  5. Robinson CJ, Stringer SE: The splice variants of vascular endothelial growth factor and their receptors. J Cell Sci 2001;114:853–865.
  6. Holmes DI, Zachary I: The vascular endothelial growth factor family: angiogenic factors in health and disease. Genome Biol 2005;6:209.
  7. Li X, Eriksson U: Novel VEGF family members. VEGF-B, VEGF-C and VEGF-D. Int J Biochem Cell Biol 2001;33:421–426.
  8. Shibuya M: Vascular endothelial growth factor receptor-2: its unique signalling and specific ligand, VEGF-E. Cancer Sci 2003;94:751–756.
  9. Neufeld G, Cohen T, Gengrinovitch S, Poltorak Z: Vascular endothelial growth factor and its receptors. FASEB J 1999;13:9–22.
  10. Zachary I: VEGF signalling: integration and multitasking in endothelial cell biology. Biochem Soc Trans 2003;31:1171–1177.
  11. Soker S, Takashima S, Miao HQ, Neufeld G, Klagsbrun M: Neuropilin-1 is expressed by endothelial and tumor cells as an isoform-specific receptor for vascular endothelial growth factor. Cell 1998;92:735–745.
  12. Migdal M, Huppertz B, Tessler S, Comforti A, Shibuya M, Reich R, Baumann H, Neufeld G: Neuropilin-1 is a placenta growth factor-2 receptor. J Biol Chem 1998;273:22272–22278.
  13. Makinen T, Olofsson B, Karpanen T, Hellman U, Soker S, Klagsbrun M, Eriksson U, Alitalo K: Differential binding of vascular endothelial growth factor B splice and proteolytic isoforms to neuropilin-1. J Biol Chem 1999;274:21217–21222.
  14. Gluzman-Poltorak Z, Cohen T, Herzog Y, Neufeld G: Neuropilin-2 and neuropilin-1 are receptors for the 165-amino acid form of vascular endothelial growth factor (VEGF) and of placenta growth factor-2, but only neuropilin-2 functions as a receptor for the 145-amino acid form of VEGF. J Biol Chem 2000;275:18040–18045.
  15. He Z, Tessier-Lavigne M: Neuropilin is a receptor for the axonal chemorepellent Semaphorin III. Cell 1997;90:739–751.
  16. Kolodkin AL, Levengood DV, Rowe EG, Tai YT, Giger RJ, Ginty DD: Neuropilin is a semaphorin III receptor. Cell 1997;90:753–762.
  17. Fujisawa H, Kitsukawa T, Kawakami A, Takagi S, Shimizu M, Hirata T: Roles of a neuronal cell-surface molecule, neuropilin, in nerve fiber fasciculation and guidance. Cell Tissue Res 1997;290:465–470.
  18. Chen H, Chedotal A, He Z, Goodman CS, Tessier-Lavigne M: Neuropilin-2, a novel member of the neuropilin family, is a high affinity receptor for the semaphorins Sema E and Sema IV but not Sema III. Neuron 1997;19:547–559.
  19. Chen H, He Z, Bagri A, Tessier-Lavigne M: Semaphorin-neuropilin interactions underlying sympathetic axon responses to class III semaphorins. Neuron 1998;21:1283–1290.
  20. Giger RJ, Urquhart ER, Gillespie SK, Levengood DV, Ginty DD, Kolodkin AL: Neuropilin-2 is a receptor for semaphorin IV: insight into the structural basis of receptor function and specificity. Neuron 1998;21:1079–1092.
  21. Gu C, Yoshida Y, Livet J, Reimert DV, Mann F, Merte J, Henderson CE, Jessell TM, Kolodkin AL, Ginty DD: Semaphorin 3E and plexin-D1 control vascular pattern independently of neuropilins. Science 2005;307:265–268.
  22. Kitsukawa T, Shimono A, Kawakami A, Kondoh H, Fujisawa H: Overexpression of a membrane protein, neuropilin, in chimeric mice causes anomalies in the cardiovascular system, nervous system and limbs. Development 1995;121:4309–4318.
  23. Kawasaki T, Kitsukawa T, Bekku Y, Matsuda Y, Sanbo M, Yagi T, Fujisawa H: A requirement for neuropilin-1 in embryonic vessel formation. Development 1999;126:4895–4902.
  24. Takashima S, Kitakaze M, Asakura M, Asanuma H, Sanada S, Tashiro F, Niwa H, Miyazaki Ji J, Hirota S, Kitamura Y, Kitsukawa T, Fujisawa H, Klagsbrun M, Hori M: Targeting of both mouse neuropilin-1 and neuropilin-2 genes severely impairs developmental yolk sac and embryonic angiogenesis. Proc Natl Acad Sci USA 2002;99:3657–3662.
  25. Dumont DJ, Fong GH, Puri MC, Gradwohl G, Alitalo K, Breitman ML: Vascularization of the mouse embryo: a study of flk-1, tek, tie, and vascular endothelial growth factor expression during development. Dev Dyn 1995;203:80–92.
  26. Millauer B, Wizigmann-Voos S, Schnurch H, Martinez R, Moller NP, Risau W, Ullrich A: High affinity VEGF binding and developmental expression suggest Flk-1 as a major regulator of vasculogenesis and angiogenesis. Cell 1993;72:835–846.
  27. Breier G, Clauss M, Risau W: Coordinate expression of vascular endothelial growth factor receptor-1 (flt-1) and its ligand suggests a paracrine regulation of murine vascular development. Dev Dyn 1995;204:228–239.
  28. Ogunshola OO, Stewart WB, Mihalcik V, Solli T, Madri JA, Ment LR: Neuronal VEGF expression correlates with angiogenesis in postnatal developing rat brain. Brain Res Dev Brain Res 2000;119:139–153.
  29. Monacci WT, Merrill MJ, Oldfield EH: Expression of vascular permeability factor/vascular endothelial growth factor in normal rat tissues. Am J Physiol 1993;264:C995–C1002.
  30. Naito S, Chang L, Pettigrew K, Ishihara S, Brightman M: Conditions that may determine blood vessel phenotype in tissues grafted to brain. Exp Neurol 1995;134:230–243.
  31. Ferrara N, Houck K, Jakeman L, Leung DW: Molecular and biological properties of the vascular endothelial growth factor family of proteins. Endocr Rev 1992;13:18–32.
  32. Stone J, Itin A, Alon T, Pe’er J, Gnessin H, Chan-Ling T, Keshet E: Development of retinal vasculature is mediated by hypoxia-induced vascular endothelial growth factor expression by neuroglia. J Neurosci 1995;15:4738–4747.
  33. Ijichi A, Sakuma S, Tofilon PJ: Hypoxia-induced vascular endothelial growth factor expression in normal rat astrocyte cultures. Glia 1995;14:87–93.
  34. Sinor AD, Irvin SM, Cobbs CS, Chen J, Graham SH, Greenberg DA: Hypoxic induction of vascular endothelial growth factor protein in astroglial cultures. Brain Res 1998;812:289–291.
  35. Bartholdi D, Rubin BP, Schwab ME: VEGF mRNA induction correlates with changes in the vascular architecture upon spinal cord damage in the rat. Eur J Neurosci 1997;9:2549–2560.
  36. Krum JM, Rosenstein JM: VEGF mRNA and its receptor flt-1 are expressed in reactive astrocytes following neural grafting and tumor cell implantation in the adult CNS. Exp Neurol 1998;154:57–65.
  37. Samii A, Unger J, Lange W: Vascular endothelial growth factor expression in peripheral nerves and dorsal root ganglia in diabetic neuropathy in rats. Neurosci Lett 1999;262:159–162.
  38. Rosenstein JM, Mani N, Silverman WF, Krum JM: Patterns of brain angiogenesis after vascular endothelial growth factor administration in vitro and in vivo. Proc Natl Acad Sci USA 1998;95:7086–7091.
  39. Silverman WF, Krum JM, Mani N, Rosenstein JM: Vascular, glial and neuronal effects of vascular endothelial growth factor in mesencephalic explant cultures. Neuroscience 1999;90:1529–1541.
  40. Sondell M, Lundborg G, Kanje M: Vascular endothelial growth factor has neurotrophic activity and stimulates axonal outgrowth, enhancing cell survival and Schwann cell proliferation in the peripheral nervous system. J Neurosci 1999;19:5731–5740.
  41. Sondell M, Lundborg G, Kanje M: Vascular endothelial growth factor stimulates Schwann cell invasion and neovascularization of acellular nerve grafts. Brain Res 1999;846:219–228.
  42. Forstreuter F, Lucius R, Mentlein R: Vascular endothelial growth factor induces chemotaxis and proliferation of microglial cells. J Neuroimmunol 2002;132:93–98.
  43. Zhu Y, Jin K, Mao XO, Greenberg DA: Vascular endothelial growth factor promotes proliferation of cortical neuron precursors by regulating E2F expression. FASEB J 2003;17:186–193.
  44. Jin K, Zhu Y, Sun Y, Mao XO, Xie L, Greenberg DA: Vascular endothelial growth factor stimulates neurogenesis in vitro and in vivo. Proc Natl Acad Sci USA 2002;99:11946–11950.
  45. Jin KL, Mao XO, Greenberg DA: Vascular endothelial growth factor: direct neuroprotective effect in in vitro ischemia. Proc Natl Acad Sci USA 2000;97:10242–10247.
  46. Matsuzaki H, Tamatani M, Yamaguchi A, Namikawa K, Kiyama H, Vitek MP, Mitsuda N, Tohyama M: Vascular endothelial growth factor rescues hippocampal neurons from glutamate-induced toxicity: signal transduction cascades. FASEB J 2001;15:1218–1220.
  47. Qiu MH, Zhang R, Sun FY: Enhancement of ischemia-induced tyrosine phosphorylation of Kv1.2 by vascular endothelial growth factor via activation of phosphatidylinositol 3-kinase. J Neurochem 2003;87:1509–1517.
  48. Sondell M, Sundler F, Kanje M: Vascular endothelial growth factor is a neurotrophic factor which stimulates axonal outgrowth through the flk-1 receptor. Eur J Neurosci 2000;12:4243–4254.
  49. Cheng L, Jia H, Löhr M, Bagherzadeh A, Holmes DIR, SelwoodD, ZacharyI: Anti-chemorepulsive effects of vascular endothelial growth factor and placental growth factor-2 in dorsal root ganglion neurons are mediated via neuropilin-1 and cyclooxygenase-derived prostanoid production. J Biol Chem 2004;279:30654–30661.
  50. Bocker-Meffert S, Rosenstiel P, Rohl C, Warneke N, Held-Feindt J, Sievers J, Lucius R: Erythropoietin and VEGF promote neural outgrowth from retinal explants in postnatal rats. Invest Ophthalmol Vis Sci 2002;43:2021–2026.
  51. Yang K, Cepko CL: Flk-1, a receptor for vascular endothelial growth factor, is expressed by retinal progenitor cells. J Neurosci 1996;16:6089–6099.
  52. Maurer MH, Tripps WK, Feldmann RE Jr, Kuschinsky W: Expression of vascular endothelial growth factor and its receptors in rat neural stem cells. Neurosci Lett 2003;344:165–168.
  53. Schanzer A, Wachs FP, Wilhelm D, Acker T, Cooper-Kuhn C, Beck H, Winkler J, Aigner L, Plate KH, Kuhn HG: Direct stimulation of adult neural stem cells in vitro and neurogenesis in vivo by vascular endothelial growth factor. Brain Pathol 2004;14:237–248.
  54. Zhang H, Vutskits L, Pepper MS, Kiss JZ: VEGF is a chemoattractant for FGF-2-stimulated neural progenitors. J Cell Biol 2003;163:1375–1384.
  55. Bagnard D, Vaillant C, Khuth ST, Dufay N, Lohrum M, Puschel AW, Belin MF, Bolz J, Thomasset N: Semaphorin 3A-vascular endothelial growth factor-165 balance mediates migration and apoptosis of neural progenitor cells by the recruitment of shared receptor. J Neurosci 2001;21:3332–3341.
  56. Jin KL, Mao XO, Greenberg DA: Vascular endothelial growth factor rescues HN33 neural cells from death induced by serum withdrawal. J Mol Neurosci 2000;14:197–203.
  57. Wick A, Wick W, Waltenberger J, Weller M, Dichgans J, Schulz JB: Neuroprotection by hypoxic preconditioning requires sequential activation of vascular endothelial growth factor receptor and Akt. J Neurosci 2002;22:6401–6407.
  58. Jin K, Mao XO, Batteur SP, McEachron E, Leahy A, Greenberg DA: Caspase-3 and the regulation of hypoxic neuronal death by vascular endothelial growth factor. Neuroscience 2001;108:351–358.
  59. Svensson B, Peters M, Konig HG, Poppe M, Levkau B, Rothermundt M, Arolt V, Kogel D, Prehn JH: Vascular endothelial growth factor protects cultured rat hippocampal neurons against hypoxic injury via an antiexcitotoxic, caspase-independent mechanism. J Cereb Blood Flow Metab 2002;22:1170–1175.
  60. Ogunshola OO, Antic A, Donoghue MJ, Fan SY, Kim H, Stewart WB, Madri JA, Ment LR: Paracrine and autocrine functions of neuronal vascular endothelial growth factor in the central nervous system. J Biol Chem 2002;277:11410–11415.
  61. Zhu Y, Jin K, Mao XO, Greenberg DA: Vascular endothelial growth factor promotes proliferation of cortical neuron precursors by regulating E2F expression. FASEB J 2003;17:186–193.
  62. Xu JY, Zheng P, Shen DH, Yang SZ, Zhang LM, Huang YL, Sun FY: Vascular endothelial growth factor inhibits outward delayed-rectifier potassium currents in acutely isolated hippocampal neurons. Neuroscience 2003;118:59–67.
  63. Gu C, Limberg BJ, Whitaker GB, Perman B, Leahy DJ, Rosenbaum JS, Ginty DD, Kolodkin AL: Characterization of neuropilin-1 structural features that confer binding to semaphorin 3A and vascular endothelial growth factor 165. J Biol Chem 2002;277:18069–18076.
  64. Mamluk R, Gechtman Z, Kutcher ME, Gasiunas N, Gallagher J, Klagsbrun M: Neuropilin-1 binds vascular endothelial growth factor 165, placenta growth factor-2, and heparin via its b1b2 domain. J Biol Chem 2002;277:24818–24825.
  65. Oosthuyse B, Moons L, Storkebaum E, Beck H, Nuyens D, Brusselmans K, Van Dorpe J, Hellings P, Gorselink M, Heymans S, Theilmeier G, Dewerchin M, Laudenbach V, Vermylen P, Raat H, Acker T, Vleminckx V, Van Den Bosch L, Cashman N, Fujisawa H, Drost MR, Sciot R, Bruyninckx F, Hicklin DJ, Ince C, Gressens P, Lupu F, Plate KH, Robberecht W, Herbert JM, Collen D, Carmeliet P: Deletion of the hypoxia-response element in the vascular endothelial growth factor promoter causes motor neuron degeneration. Nat Genet 2001;28:131–138.
  66. Takahashi T, Fournier A, Nakamura F, Wang LH, Murakami Y, Kalb RG, Fujisawa H, Strittmatter SM: Plexin-neuropilin-1 complexes form functional semaphorin-3A receptors. Cell 1999;99:59–69.
  67. Rohm B, Rahim B, Kleiber B, Hovatta I, Puschel AW: The semaphorin 3A receptor may directly regulate the activity of small GTPases. FEBS Lett 2000;486:68–72.
  68. Zanata SM, Hovatta I, Rohm B, Puschel AW: Antagonistic effects of Rnd1 and RhoD GTPases regulate receptor activity in semaphorin 3A-induced cytoskeletal collapse. J Neurosci 2002;22:471–477.
  69. Castellani V, Chedotal A, Schachner M, Faivre-Sarrailh C, Rougon G: Analysis of the L1-deficient mouse phenotype reveals cross-talk between Sema3A and L1 signaling pathways in axonal guidance. Neuron 2000;27:237–249.
  70. Kamiguchi H, Lemmon V: Neural cell adhesion molecule L1: signaling pathways and growth cone motility. J Neurosci Res 1997;49:1–8.
  71. Cai H, Reed RR: Cloning and characterization of neuropilin-1-interacting protein: a PSD-95/Dlg/ZO-1 domain-containing protein that interacts with the cytoplasmic domain of neuropilin-1. J Neurosci 1999;19:6519–6527.
  72. Gu C, Rodriguez ER, Reimert DV, Shu T, Fritzsch B, Richards LJ, Kolodkin AL, Ginty DD: Neuropilin-1 conveys semaphorin and VEGF signaling during neural and cardiovascular development. Dev Cell 2003;5:45–57.
  73. Shimizu M, Murakami Y, Suto F, Fujisawa H: Determination of cell adhesion sites of neuropilin-1. J Cell Biol 2000;148:1283–1293.
  74. Murga M, Fernandez-Capetillo O, Tosato G: Neuropilin-1 regulates attachment in human endothelial cells independently of vascular endothelial growth factor receptor-2. Blood 2005;105:1992–1999.
  75. Shima DT, Mailhos C: Vascular developmental biology: Getting nervous. Curr Opin Genet Dev 2000;10:536–542.
  76. Carmeliet P: Blood vessels and nerves: common signals, pathways and diseases. Nat Rev Genet 2003;4:710–720.
  77. Honma Y, Araki T, Gianino S, Bruce A, Heuckeroth R, Johnson E, Milbrandt J: Artemin is a vascular-derived neurotropic factor for developing sympathetic neurons. Neuron 2002;35:267–282.
  78. Carmeliet P, Ferreira V, Breier G, Pollefeyt S, Kieckens L, Gertsenstein M, Fahrig M, Vandenhoeck A, Harpal K, Eberhardt C, Declercq C, Pawling J, Moons L, Collen D, Risau W, Nagy A: Abnormal blood vessel development and lethality in embryos lacking a single VEGF allele. Nature 1996;380:435–439.
  79. Ferrara N, Carver-Moore K, Chen H, Dowd M, Lu L, O’Shea KS, Powell-Braxton L, Hillan KJ, Moore MW: Heterozygous embryonic lethality induced by targeted inactivation of the VEGF gene. Nature 1996;380:439–442.
  80. Shalaby F, Rossant J, Yamaguchi TP, Gertsenstein M, Wu XF, Breitman ML, Schuh AC: Failure of blood-island formation and vasculogenesis in Flk-1-deficient mice. Nature 1995;376:62–66.
  81. Fong GH, Rossant J, Gersenstein M, Breitman ML: Role of the Flt-1 receptor tyrosine kinase in regulating the assembly of vascular endothelium. Nature 1995;376:66–70.
  82. Carmeliet P, Ng YS, Nuyens D, Theilmeier G, Brusselmans K, Cornelissen I, Ehler E, Kakkar VV, Stalmans I, Mattot V, Perriard JC, Dewerchin M, Flameng W, Nagy A, Lupu F, Moons L, Collen D, D’Amore PA, Shima DT: Impaired myocardial angiogenesis and ischemic cardiomyopathy in mice lacking the vascular endothelial growth factor isoforms VEGF164 and VEGF188. Nat Med 1999;5:495–502.
  83. Maes C, Carmeliet P, Moermans K, Stockmans I, Smets N, Collen D, Bouillon R, Carmeliet G: Impaired angiogenesis and endochondral bone formation in mice lacking the vascular endothelial growth factor isoforms VEGF164 and VEGF188. Mech Dev 2002;111:61–73.
  84. Stalmans I, Ng YS, Rohan R, Fruttiger M, Bouche A, Yuce A, Fujisawa H, Hermans B, Shani M, Jansen S, Hicklin D, Anderson DJ, Gardiner T, Hammes HP, Moons L, Dewerchin M, Collen D, Carmeliet P, D’Amore PA: Arteriolar and venular patterning in retinas of mice selectively expressing VEGF isoforms. J Clin Invest 2002;109:327–336.
  85. Schwarz Q, Gu C, Fujisawa H, Sabelko K, Gertsenstein M, Nagy A, Taniguchi M, Kolodkin AL, Ginty DD, Shima DT, Ruhrberg C: Vascular endothelial growth factor controls neuronal migration and cooperates with Sema3A to pattern distinct compartments of the facial nerve. Genes Dev 2004;18:2822–2834.
  86. Palmer TD, Willhoite AR, Gage FH: Vascular niche for adult hippocampal neurogenesis. J Comp Neurol 2000;425:479–494.
  87. Louissaint A Jr, Rao S, Leventhal C, Goldman SA: Coordinated interaction of neurogenesis and angiogenesis in the adult songbird brain. Neuron 2002;34:945–960.
  88. Wurmser AE, Palmer TD, Gage FH: Neuroscience. Cellular interactions in the stem cell niche. Science 2004;304:1253–1255.
  89. Shen Q, Goderie SK, Jin L, Karanth N, Sun Y, Abramova N, Vincent P, Pumiglia K, Temple S: Endothelial cells stimulate self-renewal and expand neurogenesis of neural stem cells. Science 2004;304:1338–1340.
  90. Raab S, Beck H, Gaumann A, Yuce A, Gerber HP, Plate K, Hammes HP, Ferrara N, Breier G: Impaired brain angiogenesis and neuronal apoptosis induced by conditional homozygous inactivation of vascular endothelial growth factor. Thromb Haemost 2004;91:595–605.
  91. Martin P, Lewis J: Origins of the neurovascular bundle: interactions between developing nerves and blood vessels in embryonic chick skin. Int J Dev Biol 1989;33:379–387.
  92. Mukouyama YS, Shin D, Britsch S, Taniguchi M, Anderson DJ: Sensory nerves determine the pattern of arterial differentiation and blood vessel branching in the skin. Cell 2002;109:693–705.
  93. Mukouyama YS, Gerber HP, Ferrara N, Gu C, Anderson DJ: Peripheral nerve-derived VEGF promotes arterial differentiation via neuropilin-1-mediated positive feedback. Development 2005;132:941–952.
  94. Bates D, Taylor GI, Minichiello J, Farlie P, Cichowitz A, Watson N, Klagsbrun M, Mamluk R, Newgreen DF: Neurovascular congruence results from a shared patterning mechanism that utilizes semaphoring 3a and neuropilin-1. Dev Biol 2003;255:77–98.
  95. Kutcher ME, Klagsbrun M, Mamluk R: VEGF is required for the maintenance of dorsal root ganglia blood vessels but not neurons during development. FASEB J 2004;18:1952–1954.
  96. Popovici C, Isnardon D, Birnbaum D, Roubin R: Caenorhabditis elegans receptors related to mammalian vascular endothelial growth factor receptors are expressed in neural cells. Neurosci Lett 2002;329:116–120.
  97. Duchek P, Somogyi K, Jekely G, Beccari S, Rorth P: Guidance of cell migration by the Drosophila PDGF/VEGF receptor. Cell 2001;107:17–26.
  98. Heino TI, Karpanen T, Wahlstrom G, Pulkkinen M, Eriksson U, Alitalo K, Roos C: The Drosophila VEGF receptor homolog is expressed in hemocytes. Mech Dev 2001;109:69–77.
  99. Cho NK, Keyes L, Johnson E, Heller J, Ryner L, Karim F, Krasnow MA: Developmental control of blood cell migration by the Drosophila VEGF pathway. Cell 2002;108:865–876.
  100. Sears HC, Kennedy CJ, Garrity PA: Macrophage-mediated corpse engulfment is required for normal Drosophila CNS morphogenesis. Development 2003;130:3557–3565.
  101. Seipel K, Eberhardt M, Muller P, Pescia E, Yanze N, Schmid V: Homologs of vascular endothelial growth factor and receptor, VEGF and VEGFR, in the jellyfish, Podocoryne carnea. Dev Dyn 2004;231:303–312.
  102. Hayashi T, Abe K, Suzuki H, Itoyama Y: Rapid induction of vascular endothelial growth factor gene expression after transient middle cerebral artery occlusion in rats. Stroke 1997;28:2039–2044.
  103. Lennmyr F, Ata KA, Funa K, Olsson Y, Terent A: Expression of vascular endothelial growth factor and its receptors (Flt-1 and Flk-1) following permanent and transient occlusion of the middle cerebral artery in the rat. J Neuropathol Exp Neurol 1998;57:874–882.
  104. Plate KH, Beck H, Danner S, Allegrini PR, Wiessner C: Cell type specific upregulation of vascular endothelial growth factor in an MCA-occlusion model of cerebral infarct. J Neuropathol Exp Neurol 1999;58:654–666.
  105. Jin KL, Mao XO, Nagayama T, Goldsmith PC, Greenberg DA: Induction of vascular endothelial growth factor receptors and phosphatidylinositol 3′-kinase/Akt signaling by global cerebral ischemia in the rat. Neuroscience 2000;100:713–717.
  106. Yang ZJ, Bao WL, Qiu MH, Zhang LM, Lu SD, Huang YL, Sun FY: Role of vascular endothelial growth factor in neuronal DNA damage and repair in rat brain following a transient cerebral ischemia. J Neurosci Res 2002;70:140–149.
  107. Marti HJ, Bernaudin M, Bellail A, Schoch H, Euler M, Petit E, Risau W: Hypoxia-induced vascular endothelial growth factor expression precedes neovascularization after cerebral ischemia. Am J Pathol 2000;156:965–976.
  108. Krum JM, Khaibullina A: Inhibition of endogenous VEGF impedes revascularization and astroglial proliferation: roles for VEGF in brain repair. Exp Neurol 2003;181:241–257.
  109. Cheng SY, Nagane M, Huang HS, Cavenee WK: Intracerebral tumor-associated hemorrhage caused by overexpression of the vascular endothelial growth factor isoforms VEGF121 and VEGF165 but not VEGF189. Proc Natl Acad Sci USA 1997;94:12081–12087.
  110. Van Bruggen N, Thibodeaux H, Palmer JT, Lee WP, Fu L, Cairns B, Tumas D, Gerlai R, Williams SP, van Lookeren Campagne M, Ferrara N: VEGF antagonism reduces edema formation and tissue damage after ischemia/reperfusion injury in the mouse brain. J Clin Invest 1999;104:1613–1620.
  111. Zhang ZG, Zhang L, Jiang Q, Zhang R, Davies K, Powers C, Bruggen N, Chopp M: VEGF enhances angiogenesis and promotes blood-brain barrier leakage in the ischemic brain. J Clin Invest 2000;106:829–838.
  112. Hayashi T, Abe K, Itoyama Y: Reduction of ischemic damage by application of vascular endothelial growth factor in rat brain after transient ischemia. J Cereb Blood Flow Metab 1998;18:887–895.
  113. Harrigan MR, Ennis SR, Sullivan SE, Keep RF: Effects of intraventricular infusion of vascular endothelial growth factor on cerebral blood flow, edema, and infarct volume. Acta Neurochir (Wien) 2003;145:49–53.
  114. Harrigan MR, Ennis SR, Masada T, Keep RF: Intraventricular infusion of vascular endothelial growth factor promotes cerebral angiogenesis with minimal brain edema. Neurosurgery 2002;50:589–598.
  115. Sun Y, Jin K, Xie L, Childs J, Mao XO, Logvinova A, Greenberg DA: VEGF-induced neuroprotection, neurogenesis, and angiogenesis after focal cerebral ischemia. J Clin Invest 2003;111:1843–1851.
  116. Sun Y, Jin K, Childs JT, Xie L, Mao XO, Greenberg DA: Increased severity of cerebral ischemic injury in vascular endothelial growth factor-B-deficient mice. J Cereb Blood Flow Metab 2004;24:1146–1152.
  117. Beck H, Acker T, Puschel AW, Fujisawa H, Carmeliet P, Plate KH: Cell type-specific expression of neuropilins in an MCA-occlusion model in mice suggests a potential role in post-ischemic brain remodeling. J Neuropathol Exp Neurol 2002;61:339–350.
  118. Schratzberger P, Walter DH, Rittig K, Bahlmann FH, Pola R, Curry C, Silver M, Krainin JG, Weinberg DH, Ropper AH, Isner JM: Reversal of experimental diabetic neuropathy by VEGF gene transfer. J Clin Invest 2001;107:1083–1092.
  119. Schratzberger P, Schratzberger G, Silver M, Curry C, Kearney M, Magner M, Alroy J, Adelman LS, Weinberg DH, Ropper AH, Isner JM: Favorable effect of VEGF gene transfer on ischemic peripheral neuropathy. Nat Med 2000;6:405–413.
  120. Wang Y, Kilic E, Kilic U, Weber B, Bassetti CL, Marti HH, Hermann DM: VEGF overexpression induces post-ischaemic neuroprotection, but facilitates haemodynamic steal phenomena. Brain 2005;128:52–63.
  121. Vaquero J, Zurita M, de Oya S, Coca S: Vascular endothelial growth/permeability factor in spinal cord injury. J Neurosurg Spine 1999;90:220–223.
  122. Skold M, Cullheim S, Hammarberg H, Piehl F, Suneson A, Lake S, Sjogren A, Walum E, Risling M: Induction of VEGF and VEGF receptors in the spinal cord after mechanical spinal injury and prostaglandin administration. Eur J Neurosci 2000;12:3675–3686.
  123. Hobson MI, Green CJ, Terenghi G: VEGF enhances intraneural angiogenesis and improves nerve regeneration after axotomy. J Anat 2000;197:591–605.
  124. Facchiano F, Fernandez E, Mancarella S, Maira G, Miscusi M, D’Arcangelo D, Cimino-Reale G, Falchetti ML, Capogrossi MC, Pallini R: Promotion of regeneration of corticospinal tract axons in rats with recombinant vascular endothelial growth factor alone and combined with adenovirus coding for this factor. J Neurosurg 2002;97:161–168.
  125. Widenfalk J, Lipson A, Jubran M, Hofstetter C, Ebendal T, Cao Y, Olson L: Vascular endothelial growth factor improves functional outcome and decreases secondary degeneration in experimental spinal cord contusion injury. Neuroscience 2003;120:951–960.
  126. Benton RL, Whittemore SR: VEGF165 therapy exacerbates secondary damage following spinal cord injury. Neurochem Res 2003;28:1693–1703.
  127. Rowland LP, Shneider NA: Amyotrophic lateral sclerosis. N Engl J Med 2001;344:1688–1700.
  128. Cleveland DW, Rothstein JD: From Charcot to Lou Gehrig: deciphering selective motor neuron death in ALS. Nat Rev Neurosci 2001;2:806–819.
  129. Murakami T, Ilieva H, Shiote M, Nagata T, Nagano I, Shoji M, Abe K: Hypoxic induction of vascular endothelial growth factor is selectively impaired in mice carrying the mutant SOD1 gene. Brain Res 2003;989:231–237.
  130. Lambrechts D, Storkebaum E, Morimoto M, Del-Favero J, Desmet F, Marklund SL, Wyns S, Thijs V, Andersson J, van Marion I, Al-Chalabi A, Bornes S, Musson R, Hansen V, Beckman L, Adolfsson R, Pall HS, Prats H, Vermeire S, Rutgeerts P, Katayama S, Awata T, Leigh N, Lang-Lazdunski L, Dewerchin M, Shaw C, Moons L, Vlietinck R, Morrison KE, Robberecht W, Van Broeckhoven C, Collen D, Andersen PM, Carmeliet P: VEGF is a modifier of amyotrophic lateral sclerosis in mice and humans and protects motoneurons against ischemic death. Nat Genet 2003;34:383–394.
  131. Storkebaum E, Lambrechts D, Dewerchin M, Moreno-Murciano MP, Appelmans S, Oh H, Van Damme P, Rutten B, Man WY, De Mol M, Wyns S, Manka D, Vermeulen K, Van Den Bosch L, Mertens N, Schmitz C, Robberecht W, Conway EM, Collen D, Moons L, Carmeliet P: Treatment of motoneuron degeneration by intracerebroventricular delivery of VEGF in a rat model of ALS. Nat Neurosci 2005;8:85–92.
  132. Azzouz M, Ralph GS, Storkebaum E, Walmsley LE, Mitrophanous KA, Kingsman SM, Carmeliet P, Mazarakis ND: VEGF delivery with retrogradely transported lentivector prolongs survival in a mouse ALS model. Nature 2004;429:413–417.
  133. Sopher BL, Thomas PS Jr, LaFevre-Bernt MA, Holm IE, Wilke SA, Ware CB, Jin LW, Libby RT, Ellerby LM, La Spada AR: Androgen receptor YAC transgenic mice recapitulate SBMA motor neuronopathy and implicate VEGF164 in the motor neuron degen eration. Neuron 2004;41:687–699.
  134. Perlmutter LS, Chui HC: Microangiopathy, the vascular basement membrane and Alzheimer’s disease: a review. Brain Res Bull 1990;24:677–686.
  135. Kalaria RN: Small vessel disease and Alzheimer’s dementia: pathological considerations. Cerebrovasc Dis 2002;13(suppl 2):48–52.
  136. Ho KL, Garcia JH: Neuropathology of the small blood vessels in selected diseases of the cerebral white matter; in Pantoni L, Inzitari D, Wallin A (eds): The Matter of White Matter. Dordrecht, ICG Publications, 2000, pp 247–273.
  137. Kalaria RN, Kenny RA, Ballard CG, Perry R, Ince P, Polvikoski T: Towards defining the neuropathological substrates of vascular dementia. J Neurol Sci 2004;226:75–80.
  138. Kalaria RN, Cohen DL, Premkumar DR, Nag S, LaManna JC, Lust WD: Vascular endothelial growth factor in Alzheimer’s disease and experimental cerebral ischemia. Brain Res Mol Brain Res 1998;12;62:101–105.
  139. Stopa EG, Berzin TM, Kim S, Song P, Kuo-LeBlanc V, Rodriguez-Wolf M, Baird A, Johanson CE: Human choroid plexus growth factors: What are the implications for CSF dynamics in Alzheimer’s disease? Exp Neurol 2001;167:40–47.
  140. Tarkowski E, Issa R, Sjogren M, Wallin A, Blennow K, Tarkowski A, Kumar P: Increased intrathecal levels of the angiogenic factors VEGF and TGF-β in Alzheimer’s disease and vascular dementia. Neurobiol Aging 2002;23:237–243.
  141. Colangelo V, Schurr J, Ball MJ, Pelaez RP, Bazan NG, Lukiw WJ: Gene expression profiling of 12633 genes in Alzheimer hippocampal CA1: transcription and neurotrophic factor down-regulation and up-regulation of apoptotic and pro-inflammatory signaling. J Neurosci Res 2002;70:462–473.
  142. Pogue AI, Lukiw WJ: Angiogenic signaling in Alzheimer’s disease. Neuroreport 2004;15:1507–1510.
  143. Yang SP, Bae DG, Kang HJ, Gwag BJ, Gho YS, Chae CB: Co-accumulation of vascular endothelial growth factor with β-amyloid in the brain of patients with Alzheimer’s disease. Neurobiol Aging 2004;25:283–290.
  144. Yasuhara T, Shingo T, Kobayashi K, Takeuchi A, Yano A, Muraoka K, Matsui T, Miyoshi Y, Hamada H, Date I: Neuroprotective effects of vascular endothelial growth factor upon dopaminergic neurons in a rat model of Parkinson’s disease. Eur J Neurosci 2004;19:1494–1504.
  145. Feiner L, Webber AL, Brown CB, Lu MM, Jia L, Feinstein P, Mombaerts P, Epstein JA, Raper JA: Targeted disruption of semaphorin 3C leads to persistent truncus arteriosus and aortic arch interruption. Development 2001;128:3061–3070.
  146. Toyofuku T, Zhang H, Kumanogoh A, Takegahara N, Suto F, Kamei J, Aoki K, Yabuki M, Hori M, Fujisawa H, Kikutani H: Dual roles of Sema6D in cardiac morphogenesis through region-specific association of its receptor, plexin-A1, with off-track and vascular endothelial growth factor receptor type 2. Genes Dev 2004;18:435–447.