Vascular Endothelial Growth Factor (VEGF) in Seizures:

A Double-Edged Sword
  • Susan D. Croll
  • Jeffrey H. Goodman
  • Helen E. Scharfman
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 548)


Vascular endothelial growth factor (VEGF) is a vascular growth factor which induces angiogenesis (the development of new blood vessels), vascular permeability, and inflammation. In brain, receptors for VEGF have been localized to vascular endothelium, neurons, and glia. VEGF is upregulated after hypoxic injury to the brain, which can occur during cerebral ischemia or high-altitude edema, and has been implicated in the blood-brain barrier breakdown associated with these conditions. Given its recently-described role as an inflammatory mediator, VEGF could also contribute to the inflammatory responses observed in cerebral ischemia. After seizures, blood-brain barrier breakdown and inflammation is also observed in brain, albeit on a lower scale than that observed after stroke. Recent evidence has suggested a role for inflammation in seizure disorders. We have described striking increases in VEGF protein in both neurons and glia after pilocarpine-induced status epilepticus in the brain. Increases in VEGF could contribute to the blood-brain barrier breakdown and inflammation observed after seizures. However, VEGF has also been shown to be neuroprotective across several experimental paradigms, and hence could potentially protect vulnerable cells from damage associated with seizures. Therefore, the role of VEGF after seizures could be either protective or destructive. Although only further research will determine the exact nature of VEGF’s role after seizures, preliminary data indicate that VEGF plays a protective role after seizures.


Vascular Endothelial Growth Factor Cerebral Ischemia Status Epilepticus Middle Cerebral Artery Occlusion Focal Cerebral Ischemia 
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  1. 1.
    Gotoh O, Asano T, Koide T et al. Ischemic brain edema following occlusions of the middle cerebral artery in the rat. I: The time courses of the brain water, sodium and potassium contents and blood-brain barrier permeability to 125I-albumin. Stroke 1985; 16: 101–109.PubMedCrossRefGoogle Scholar
  2. 2.
    Hatashita S, Hoff JT. Role of blood-brain barrier permeability in focal ischemic brain edema. Adv Neurol 1990; 52: 327–333.PubMedGoogle Scholar
  3. 3.
    Hatashita S, Hoff JT. Brain edema and cerebrovascular permeability during cerebral ischemia in rats. Stroke 1990; 21: 582–588.PubMedCrossRefGoogle Scholar
  4. 4.
    Nakagawa Y, Fujimoto N, Matsumoto K et al. Morphological changes in acute cerebral ischemia after occlusion and reperfusion in the rat. Adv Neurol 1990; 52: 21–27.PubMedGoogle Scholar
  5. 5.
    Kitagawa K, Matsumoto M, Tagaya M et al. Temporal profile of serum albumin extravasation following cerebral ischemia in a newly established reproducible gerbil model for vasogenic brain edema: a combined immunohistochemical and dye tracer analysis. Acta Neuropathol (Berl) 1991; 82: 164–171.CrossRefGoogle Scholar
  6. 6.
    Menzies SA, Betz AL, Hoff JT. Contributions of ions and albumin to the formation and resolution of ischemic brain edema. J Neurosurg 1993; 78: 257–266.PubMedCrossRefGoogle Scholar
  7. 7.
    Matsumoto K, Lo EH, Pierce AR et al. Role of vasogenic edema and tissue cavitation in ischemic evolution on diffusion-weighted imaging: comparison with multiparameter MR and immunohistochemistry. Am J Neuroradiol 1995; 16: 1107–1115.PubMedGoogle Scholar
  8. 8.
    Rosenberg GA. Ischemic brain edema. Prog Cardiovasc Dis 1999; 42: 209–216.PubMedCrossRefGoogle Scholar
  9. 9.
    Ates N, Esen N, Ilbay G. Absence epilepsy and regional blood-brain barrier permeability: the effects of pentylenetetrazole-induced convulsions. Pharmacol Res 1999; 39: 305–310.PubMedCrossRefGoogle Scholar
  10. 10.
    Cornford EM. Epilepsy and the blood brain barrier: endothelial cell responses to seizures. Adv Neurol 1999; 79: 845–862.PubMedGoogle Scholar
  11. 11.
    Roch C, Leroy C, Nehlig A et al. Magnetic resonance imaging in the study of the lithium-pilocarpine model of temporal lobe epilepsy in adult rats. Epilepsia 2002; 43: 325–335.PubMedCrossRefGoogle Scholar
  12. 12.
    Feuerstein GZ, Wang X, Barone FC. Inflammatory gene expression in cerebral ischemia and trauma. Potential new therapeutic targets. Ann NY Acad Sci 1997; 825, 179–193.PubMedCrossRefGoogle Scholar
  13. 13.
    del Zoppo GJ, Wagner S, Tagaya M. Trends and future developments in the pharmacological treatment of acute ischaemic stroke. Drugs 1997; 54: 9–38.PubMedCrossRefGoogle Scholar
  14. 14.
    Becker KJ. Inflammation and acute stroke. Curr Opin Neurol 1998; 11: 45–49.PubMedCrossRefGoogle Scholar
  15. 15.
    DeGraba TJ. The role of inflammation after acute stroke: utility of pursuing anti-adhesion molecule therapy. Neurology 1998; 51: S62–68.PubMedCrossRefGoogle Scholar
  16. 16.
    Jean WC, Spellman SR, Nussbaum ES et al. Reperfusion injury after focal cerebral ischemia: the role of inflammation and the therapeutic horizon. Neurosurgery 1998; 43: 1382–1396.PubMedGoogle Scholar
  17. 17.
    del Zoppo GJ, Hallenbeck JM. Advances in the vascular pathophysiology of ischemic stroke. Thromb Res 2000; 98: 73–81.PubMedCrossRefGoogle Scholar
  18. 18.
    Stanimirovic D, Satoh K. Inflammatory mediators of cerebral endothelium: a role in ischemic brain inflammation. Brain Pathol 2000; 10: 3–126.Google Scholar
  19. 19.
    Zhang RL, Chopp M, Jiang N et al. Anti-intercellular adhesion molecule-1 antibody reduces ischemic cell damage after transient but not permanent middle cerebral artery occlusion in the Wistar rat. Stroke 1995; 26: 1438–1442.PubMedCrossRefGoogle Scholar
  20. 20.
    Chopp M, Li Y, Jiang N et al. Antibodies against adhesion molecules reduce apoptosis after transient middle cerebral artery occlusion in rat brain. J Cereb Blood Flow Metab 1996; 16: 578–584.PubMedCrossRefGoogle Scholar
  21. 21.
    Chopp M, Zhang ZG. Anti-adhesion molecule and nitric oxide protection strategies in ischemic stroke. Curr Opin Neurol 1996; 9: 68–72.PubMedCrossRefGoogle Scholar
  22. 22.
    Goussev AV, Zhang Z, Anderson DC et al. P-selectin antibody reduces hemorrhage and infarct volume resulting from MCA occlusion in the rat. J Neurol Sci 1998; 161: 16–22.PubMedCrossRefGoogle Scholar
  23. 23.
    Jiang N, Chopp M, Chahwala S. Neutrophil inhibitory factor treatment of focal cerebral ischemia in the rat. Brain Res 1998; 788: 25–34.PubMedCrossRefGoogle Scholar
  24. 24.
    Peltola J, Laaksonen J, Haapala AM et al. Indicators of inflammation after recent tonic-clonic epileptic seizures correlate with plasma interleukin-6 levels. Seizure 2002; 11: 44–46.PubMedCrossRefGoogle Scholar
  25. 25.
    Vezzani A, Conti M, De Luigi A et al. Interleukin-lbeta immunoreactivity and microglia are enhanced in the rat hippocampus by focal kainate application: functional evidence for enhancement of electrographic seizures. J Neurosci 1999; 19: 5054–5065.PubMedGoogle Scholar
  26. 26.
    De Simoni MG, Perego C, Ravizza T et al. Inflammatory cytokines and related genes are induced in the rat hippocampus by limbic status epilepticus. Eur J Neurosci 2000; 12: 2623–2633.PubMedCrossRefGoogle Scholar
  27. 27.
    Vezzani A, Moneta D, Conti M et al. Powerful anticonvulsant action of IL-1 receptor antagonist on intracerebral injection and astrocytic overexpression in mice. Proc Nail Acad Sci USA 2000; 97: 11534–11539.CrossRefGoogle Scholar
  28. 28.
    Vezzani A, Moneta D, Richichi C et al. Functional role of inflammatory cytokines and antiinflammatory molecules in seizures and epileptogenesis. Epilepsia 2002; 43 (55): 30–35.PubMedCrossRefGoogle Scholar
  29. 29.
    Tomanek RJ, Schatteman GC, Angiogenesis. New insights and therapeutic potential. Anat Rec 2000; 261: 126–135.PubMedCrossRefGoogle Scholar
  30. 30.
    Yancopoulos GD, Davis S, Gale NW et al. Vascular-specific growth factors and blood vessel formation. Nature 2000; 407: 242–248.PubMedCrossRefGoogle Scholar
  31. 31.
    Bednar MM, Raymond S, McAuliffe T et al. The role of neutrophils and platelets in a rabbit model of thromboembolic stroke. Stroke 1991; 22: 44–50.PubMedCrossRefGoogle Scholar
  32. 32.
    Clark RK, Lee EV, Fish CJ et al. Development of tissue damage, inflammation and resolution following stroke: an immunohistochemical and quantitative planimetric study. Brain Res Bull 1993; 31: 565–572.PubMedCrossRefGoogle Scholar
  33. 33.
    Morioka T, Kalehua AN, Streit WJ. Characterization of microglial reaction after middle cerebral artery occlusion in rat brain. J Comp Neurol 1993; 327: 123–132.PubMedCrossRefGoogle Scholar
  34. 34.
    Okada Y, Copeland BR, Mori E et al. P-selectin and intercellular adhesion molecule-1 expression after focal brain ischemia and reperfusion. Stroke 1994; 25: 202–211.PubMedCrossRefGoogle Scholar
  35. 35.
    Beck H, Acker T, Wiessner C et al. Expression of angiopoietin-1, angiopoietin-2 and tie receptors after middle cerebral artery occlusion in the rat. Amer J Pathol 2000; 157: 1473–1483.CrossRefGoogle Scholar
  36. 36.
    Marti HJ, Bernaudin M, Bellail A et al. Hypoxia-induced vascular endothelial growth factor expression precedes neovascularization after cerebral ischemia. Am J Pathol 2000; 156: 965–976.PubMedCrossRefGoogle Scholar
  37. 37.
    Schwab JM, Nguyen TD, Postler E et al. Selective accumulation of cyclooxygenase-1-expressing microglial cells/macrophages in lesions of human focal cerebral ischemia. Acta Neuropathol (Berl) 2000; 99: 609–614.CrossRefGoogle Scholar
  38. 38.
    Wang X, Yue TL, Barone FC et al. Demonstration of increased endothelial-leukocyte adhesion molecule-1 mRNA expression in rat ischemic cortex. Stroke 1995; 26: 1665–1668.PubMedCrossRefGoogle Scholar
  39. 39.
    Zubkov AY, Ogihara K, Bernanke DH et al. Apoptosis of endothelial cells in vessels affected by cerebral vasospasm. Surg Neurol 2000; 53: 260–266.PubMedCrossRefGoogle Scholar
  40. 40.
    Senger DR, Perruzzi CA, Feder J et al. A highly conserved vascular permeability factor secreted by a variety of human and rodent tumor cell lines. Cancer Res 1986; 46: 5629–5632.PubMedGoogle Scholar
  41. 41.
    Frelin C, Ladoux A, D’Angelo G. Vascular endothelial growth factors and angiogenesis. Ann Endocrinol (Paris) 2000; 61: 70–74.Google Scholar
  42. 42.
    Quinn TP, Peters KG, De Vries C et al. Fetal liver kinase 1 is a receptor for vascular endothelial growth factor and is selectively expressed in vascular endothelium. Proc Nail Acad Sci USA 1993; 90: 7533–7537CrossRefGoogle Scholar
  43. 43.
    Soker S, Takashima S, Miao H et al. Neuropilin-1 is expressed by endothelial and tumor cells as an isoform-specific receptor for vascular endothelial growth factor. Cell 1998; 92: 735–745.PubMedCrossRefGoogle Scholar
  44. 44.
    Gluzman-Poltorak Z, Cohen T, Herzog Y et al. 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. Biol Chem 2000; 275: 18040–5.CrossRefGoogle Scholar
  45. 45.
    Jin KL, Mao XO, Greenberg DA. Vascular endothelial growth factor: direct neuroprotective effect in in vivo ischemia. Proc Nail Acad Sci 2000; 97: 10242–10247.CrossRefGoogle Scholar
  46. 46.
    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.PubMedCrossRefGoogle Scholar
  47. 47.
    Groll SD, Wiegand SJ. Vascular growth factors and cerebral ischemia. Mol Neurobiol 2001; 23: 121–35.CrossRefGoogle Scholar
  48. 48.
    Krum JM, Mani N, Rosenstein JM. Angiogenic and astroglial responses to vascular endothelial growth factor administration in adult rat brain. Neuroscience 2002; 110: 589–604.PubMedCrossRefGoogle Scholar
  49. 49.
    Lennmyr F, Ata KA, Funa K et al. Expression of vascular endothelial growth factor (VEGF) 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.PubMedCrossRefGoogle Scholar
  50. 50.
    Sawano A, Iwai S, Sakurai Y et al. Flt-1, vascular endothelial growth factor receptor 1, is a novel cell surface marker for the lineage of monocyte-macrophages in humans. Blood 2001; 97: 785–791.PubMedCrossRefGoogle Scholar
  51. 51.
    Kawakami A, Kitsukawa T, Takagi S et al. Developmentally regulated expression of a cell surface protein, neuropilin, in the mouse nervous system. J Neurobiol 1996; 29: 1–17.PubMedCrossRefGoogle Scholar
  52. 52.
    Chédotal A, Del Rio JA, Ruiz M et al. Semaphorins III and IV repel hippocampal axons via two distinct receptors. Develop 1998; 125: 4313–4323.Google Scholar
  53. 53.
    Ferrara N, Davis-Smyth T. The biology of vascular endothelial growth factor. Endocr Rev 1997; 18: 4–25.PubMedCrossRefGoogle Scholar
  54. 54.
    Carmeliet P, Collen D. Molecular basis of angiogenesis. Roles of VEGF and VE-cadherin. Ann NY Acad Sci 2000; 902, 249–262.PubMedCrossRefGoogle Scholar
  55. 55.
    Dvorak HF. VPF/VEGF and the angiogenic response. Semin Perinatol 2000; 24: 75–78.PubMedCrossRefGoogle Scholar
  56. 56.
    Ferrara N, Carver-Moore K, Chen H et al. Heterozygous embryonic lethality induced by targeted inactivation of the VEGF gene. Nature 1996; 380: 439–442.PubMedCrossRefGoogle Scholar
  57. 57.
    Carmeliet P, Ferreira V, Breier G et al. Abnormal blood vessel development and lethality in embryos lacking a single VEGF allele. Nature 1996; 380: 435–9.PubMedCrossRefGoogle Scholar
  58. 58.
    Fong GH, Rossant J, Gertsenstein M et al. Role of the Flt-1 receptor tyrosine kinase in regulating the assembly of vascular endothelium. Nature 1995; 376: 66–70.PubMedCrossRefGoogle Scholar
  59. 59.
    Shalaby F, Rossant J, Yamaguchi TP et al. Failure of blood-island formation and vasculogenesis in Flk-1-deficient mice. Nature 1995; 376: 62–66.PubMedCrossRefGoogle Scholar
  60. 60.
    Banters C, Asahara T, Zheng LP et al. Physiological assessment of augmented vascularity induced by VEGF in ischemic rabbit hindlimb. Am J Physiol 1994; 267: H1263–1271.Google Scholar
  61. 61.
    Takeshita S, Zheng LP, Brogi E et al. Therapeutic angiogenesis. A single intraarterial bolus of vascular endothelial growth factor augments revascularization in a rabbit ischemic hind limb model. J Clin Invest 1994; 93: 662–670.PubMedCrossRefGoogle Scholar
  62. 62.
    Pearlman JD, Hibberd MG, Chuang ML et al. Magnetic resonance mapping demonstrates benefits of VEGF-induced myocardial angiogenesis. Nat Med 1995; 1: 1085–1089.PubMedCrossRefGoogle Scholar
  63. 63.
    Rosenstein JM, Mani N, Silverman WF et al. Patterns of brain angiogenesis after vascular endothelial growth factor administration in vivo and in vivo. Proc Nail Acad Sci USA 1998; 95: 7086–7091.CrossRefGoogle Scholar
  64. 64.
    Springer ML, Chen AS, Kraft PE et al. VEGF gene delivery to muscle: potential role for vasculogenesis in adults. Mol Cell 1998; 2: 549–558.PubMedCrossRefGoogle Scholar
  65. 65.
    Kasselman LJ, Ransohoff RM, Cai N et al. Vascular endothelial growth factor (VEGF)-mediated inflammation precedes angiogenesis in adult rat brain. Soc Nsci Abstr 2002; in press.Google Scholar
  66. 66.
    Proescholdt MA, Heiss JD, Walbridge S et al. Vascular endothelial growth factor (VEGF) modulates vascular permeability and inflammation in rat brain. J Neuropathol Exp Neurol 1999; 58: 613–627.PubMedCrossRefGoogle Scholar
  67. 67.
    Carmeliet P. VEGF gene therapy: stimulating angiogenesis or angioma-genesis? Nat Med 2000; 6: 1102–1103.PubMedCrossRefGoogle Scholar
  68. 68.
    Dobrogowska A, Lossinsky AS, Tarnawski M et al. Increased blood-brain barrier permeability and endothelial abnormalities induced by vascular endothelial growth factor. J Neurocytol 1998; 27: 63–173.CrossRefGoogle Scholar
  69. 69.
    Zhao L, Zhang MM, Ng K. Effects of vascular permeability factor on the permeability of cultured endothelial cells from brain capillaries. J Cardiovasc Pharmacol 1998; 32: 1–4.PubMedCrossRefGoogle Scholar
  70. 70.
    Kaner RJ, Ladetto JV, Singh R et al. Lung overexpression of the vascular endothelial growth factor gene induces pulmonary edema. Am J Respir Cell Mol Biol 2000; 22: 657–664.PubMedGoogle Scholar
  71. 71.
    Thurston G, Rudge JS, Ioffe E et al. Angiopoietin-1 protects the adult vasculature against plasma leakage. Nat Med 2000; 6: 460–463.PubMedCrossRefGoogle Scholar
  72. 72.
    Kovacs Z, Ikezaki K, Samoto K et al. VEGF and flt: expression time kinetics in rat brain infarct. Stroke 1996; 27: 1865–1873.PubMedCrossRefGoogle Scholar
  73. 73.
    Hayashi T, Abe K, Suzuki H et al. Rapid induction of vascular endothelial growth factor gene expression after transient middle cerebral artery occlusion in rats. Stroke 1997; 28: 2039–2044.PubMedCrossRefGoogle Scholar
  74. 74.
    Cobbs CS, Chen J, Greenberg DA et al. Vascular endothelial growth factor expression in transient focal cerebral ischemia in the rat. Neurosci Lett 1998; 249: 79–82.PubMedCrossRefGoogle Scholar
  75. 75.
    Issa R, Krupinski J, Bujny T et al. Vascular endothelial growth factor and its receptor, KDR, in human brain tissue after ischemic stroke. Lab Invest 1999; 79: 417–425.PubMedGoogle Scholar
  76. 76.
    Lee M-Y, Ju W-K, Cha J-H et al. Expression of vascular endothelial growth factor mRNA following transient forebrain ischemia in rats. Neurosci Lett 1999; 265: 107–110.PubMedCrossRefGoogle Scholar
  77. 77.
    Pichiule P, Chavez JC, Xu K et al. Vascular endothelial growth factor upregulation in transient global ischemia induced by cardiac arrest and resuscitation in rat brain. Brain Res Mol Brain Res 1999; 74: 83–90.PubMedCrossRefGoogle Scholar
  78. 78.
    Plate KH, Beck H, Danner S et al. 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.PubMedCrossRefGoogle Scholar
  79. 79.
    Lin TN, Wang CK, Cheung WM et al. Induction of angiopoietin and tie receptor mRNA expression after cerebral ischemia-reperfusion. J Cereb Blood Flow Metab 2000; 20: 387–395.PubMedCrossRefGoogle Scholar
  80. 80.
    Chiarugi V, Magnelli L, Chiarugi A et al. Hypoxia induced pivotal tumor angiogenesis control factors including p53, vascular endothelial growth factor and the NFKB-dependent inducible nitric oxide synthase and cyclo-oxygenase-2. J Cancer Res Clin Oncol 1999; 125: 525–528.PubMedCrossRefGoogle Scholar
  81. 81.
    El Awad B, Kreft B, Wolber EM et al. Hypoxia and interleukin-1 stimulate vascular endothelial growth factor production in human proximal tubular cells. Kidney Intl 2000; 58: 43–50.CrossRefGoogle Scholar
  82. 82.
    Tsuzuki Y, Fukumura D, Oosthuyse B et al. Vascular endothelial growth factor (VEGF) modulation by targeting hypoxia-inducible factor-10-hypoxia response element-VEGF cascade differentially regulates vascular response and growth rate in tumors. Cancer Res 2000; 60: 6248–6252.PubMedGoogle Scholar
  83. 83.
    Yuan HT, Yang SP, Woolf AS. Hypoxia up-regulates angiopoietin-2, a Tie-2 ligand, in mouse mesangial cells. Kidney Int 2000; 58: 1912–1919.PubMedCrossRefGoogle Scholar
  84. 84.
    Bergeron M, Yu AY, Solway KE et al. Induction of hypoxia-inducible factor-1 (HIF-1) and its target genes following focal ischaemia in rat brain. Eur J Neurosci 1999; 11: 4159–4170.PubMedCrossRefGoogle Scholar
  85. 85.
    Hossmann KA. The hypoxic brain. Insights from ischemia research. Adv Exp Med Biol 1999; 474: 155–169.PubMedCrossRefGoogle Scholar
  86. 86.
    Jander S, Schroeter M, Peters 0 et al. Cortical spreading depression induces proinflammatory cytokine gene expression in the rat brain. J Cereb Blood Flow Metab 2001; 21: 218–225.PubMedCrossRefGoogle Scholar
  87. 87.
    Scharfman HE, Goodman JH, Sollas AL et al. Spontaneous limbic seizures after intrahippocampal infusion of brain-derived neurotrophic factor. Exp Neurol 2002; 174: 201–214.PubMedCrossRefGoogle Scholar
  88. 88.
    Croll SD, Goodman JH, Sollas A et al. Vascular endothelial growth factor (VEGF) is upregulated after pilocarpine-induced seizures in rats. Soc Nsci Abs 2000; in press.Google Scholar
  89. 89.
    Sirevaag AM, Greenough WT. Differential rearing effects on rat visual cortex synapses. III. Neuronal and glial nuclei, boutons, dendrites and capillaries. Brain Res 1987; 424: 320–332.PubMedCrossRefGoogle Scholar
  90. 90.
    Carmeliet P, Storkebaum E. Vascular and neuronal effects of VEGF in the nervous system: implications for neurological disorders. Semin Cell Dev Biol 2002; 13: 39–53.PubMedCrossRefGoogle Scholar
  91. 91.
    Ogunshola 00, Antic A, Donoghue MJ et al. Paracrine and autocrine functions of neuronal vascular endothelial growth factor (VEGF) in the central nervous system. J Biol Chem 2002; 277: 11410–11415.CrossRefGoogle Scholar
  92. 92.
    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.PubMedCrossRefGoogle Scholar
  93. 93.
    Jin K, Mao X0, Batteur SP et al. Caspase-3 and the regulation of hypoxic neuronal death by vascular endothelial growth factor. Neuroscience 2001; 108: 351–358.PubMedCrossRefGoogle Scholar
  94. 94.
    Yourey PA, Gohari S, Su JL et al. Vascular endothelial cell growth factors promote the in vivo development of rat photoreceptor cells. J Neurosci 2000; 20: 6781–6788.PubMedGoogle Scholar
  95. 95.
    Robinson GS, Ju M, Shih SC et al. Nonvascular role for VEGF: VEGFR-1, 2 activity is critical for neural retinal development. FASEB J 2001; 15: 1215–1217.Google Scholar
  96. 96.
    Hobson MI, Green CJ, Terenghi G VEGF enhances intraneural angiogenesis and improves nerve regeneration after axotomy. J Anat 2000; 197: 591–605.PubMedCrossRefGoogle Scholar
  97. 97.
    Schratzberger P, Schratzberger G, Silver M et al. Favorable effect of VEGF gene transfer on ischemic peripheral neuropathy. Nat Med 2000; 6: 405–413.PubMedCrossRefGoogle Scholar
  98. 98.
    Oosthuyse B, Moons L, Storkebaum E et al. Deletion of the hypoxia-response element in the vascular endothelial growth factor promoter causes motor neuron degeneration. Nat Genet 2001; 28: 131–138.PubMedCrossRefGoogle Scholar
  99. 99.
    Matsuzaki H, Tamatani M, Yamaguchi A et al. Vascular endothelial growth factor rescues hippocampal neurons from glutamate-induced toxicity: signal transduction cascades. FASEB J 2001; 15: 1218–1220.PubMedGoogle Scholar
  100. 100.
    Mazure NM, Chen EY, Laderoute KR et al. Induction of vascular endothelial growth factor by hypoxia is modulated by a phosphatidylinositol 3-kinase/Akt signlaing pathway in Ha-ras-transformed cells through a hypoxia-inducible factor-1 transcriptional element. Blood 1997; 90: 3322–3331.PubMedGoogle Scholar
  101. 101.
    Gerber HP, McMurtrey A, Kowalski J et al. Vascular endothelial growth factor regulates endothelial cell survival through the phosphatidylinositol 3.-kinase/Akt signal transduction pathway. Requirement for Flk-1/KDR activation. J Biol Chem 1998; 273: 30336–30343.PubMedCrossRefGoogle Scholar
  102. 102.
    Wick A, Wick W, Waltenberger J et al. Neuroprotection by hypoxic preconditioning requires sequential activation of vascular endothelial growth factor receptor and Akt. J Neurosci 2002; 22: 6401–6407.PubMedGoogle Scholar
  103. 103.
    Bagnard D, Vaillant C, Khuth ST et al. 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.PubMedGoogle Scholar
  104. 104.
    Li J, Perrella MA, Tsai JC et al. Induction of vascular endothelial growth factor gene expression by interleukin-1 beta in rat aortic smooth muscle cells. J Biol Chem 1995; 270: 308–312.PubMedCrossRefGoogle Scholar
  105. 105.
    Ryuto M, Ono M, Izumi H et al. Induction of vascular endothelial growth factor by tumor necrosis factor alpha in human glioma cells. Possible roles of SP-1. J Biol Chem 1996; 271: 28220–28228.PubMedCrossRefGoogle Scholar
  106. 106.
    Jung YD, Liu W, Reinmuth N et al. Vascular endothelial growth factor is upregulated by interleukin-1 beta in human vascular smooth muscle cells via the P38 mitogen-activated protein kinase pathway. Angiogenesis 2001; 4: 155–162.PubMedCrossRefGoogle Scholar
  107. 107.
    Shandra AA, Godlevsky LS, Vastyanov RS et al. The role of TNF-alpha in amygdala kindled rats. Neurosci Res 2002; 42: 147–153.PubMedCrossRefGoogle Scholar
  108. 108.
    Zhang ZG, Zhang L, Jiang Q et al. VEGF enhances angiogenesis and promotes blood-brain barrier leakage in the ischemic brain. Clin Invest 2000; 106: 829–838.CrossRefGoogle Scholar
  109. 109.
    van Bruggen N, Thibodeaux H, Palmer JT et al. VEGF antagonism reduces edema formation and tissue damage after ischemia/reperfusion injury in the mouse brain. J Clin Invest 1999; 104: 1613–1620.PubMedCrossRefGoogle Scholar
  110. 110.
    Baik EJ, Kim EJ, Lee SH et al. Cyclooxygenase-2 selective inhibitors aggravate kainic acid induced seizure and neuronal cell death in the hippocampus. Brain Res 1999; 843: 118–129.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2004

Authors and Affiliations

  • Susan D. Croll
  • Jeffrey H. Goodman
  • Helen E. Scharfman

There are no affiliations available

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