Encapsulated vascular endothelial growth factor—secreting cell grafts have neuroprotective and angiogenic effects on focal cerebral ischemia

Akimasa Yano Department of Neurological Surgery, Okayama University Graduate School of Medicine and Dentistry, Okayama; and Department of Molecular Medicine, Sapporo Medical University, Sapporo, Japan

Search for other papers by Akimasa Yano in
Current site
Google Scholar
PubMed Close
 M.D.
,
Tetsuro Shingo Department of Neurological Surgery, Okayama University Graduate School of Medicine and Dentistry, Okayama; and Department of Molecular Medicine, Sapporo Medical University, Sapporo, Japan

Search for other papers by Tetsuro Shingo in
Current site
Google Scholar
PubMed Close
 M.D.
,
Akira Takeuchi Department of Neurological Surgery, Okayama University Graduate School of Medicine and Dentistry, Okayama; and Department of Molecular Medicine, Sapporo Medical University, Sapporo, Japan

Search for other papers by Akira Takeuchi in
Current site
Google Scholar
PubMed Close
 M.D.
,
Takao Yasuhara Department of Neurological Surgery, Okayama University Graduate School of Medicine and Dentistry, Okayama; and Department of Molecular Medicine, Sapporo Medical University, Sapporo, Japan

Search for other papers by Takao Yasuhara in
Current site
Google Scholar
PubMed Close
 M.D.
,
Kazuki Kobayashi Department of Neurological Surgery, Okayama University Graduate School of Medicine and Dentistry, Okayama; and Department of Molecular Medicine, Sapporo Medical University, Sapporo, Japan

Search for other papers by Kazuki Kobayashi in
Current site
Google Scholar
PubMed Close
 M.D.
,
Kazuya Takahashi Department of Neurological Surgery, Okayama University Graduate School of Medicine and Dentistry, Okayama; and Department of Molecular Medicine, Sapporo Medical University, Sapporo, Japan

Search for other papers by Kazuya Takahashi in
Current site
Google Scholar
PubMed Close
 M.D.
,
Kenichiro Muraoka Department of Neurological Surgery, Okayama University Graduate School of Medicine and Dentistry, Okayama; and Department of Molecular Medicine, Sapporo Medical University, Sapporo, Japan

Search for other papers by Kenichiro Muraoka in
Current site
Google Scholar
PubMed Close
 M.D.
,
Toshihiro Matsui Department of Neurological Surgery, Okayama University Graduate School of Medicine and Dentistry, Okayama; and Department of Molecular Medicine, Sapporo Medical University, Sapporo, Japan

Search for other papers by Toshihiro Matsui in
Current site
Google Scholar
PubMed Close
 M.D.
,
Yasuyuki Miyoshi Department of Neurological Surgery, Okayama University Graduate School of Medicine and Dentistry, Okayama; and Department of Molecular Medicine, Sapporo Medical University, Sapporo, Japan

Search for other papers by Yasuyuki Miyoshi in
Current site
Google Scholar
PubMed Close
 M.D.
,
Hirofumi Hamada Department of Neurological Surgery, Okayama University Graduate School of Medicine and Dentistry, Okayama; and Department of Molecular Medicine, Sapporo Medical University, Sapporo, Japan

Search for other papers by Hirofumi Hamada in
Current site
Google Scholar
PubMed Close
 M.D.
, and
Isao Date Department of Neurological Surgery, Okayama University Graduate School of Medicine and Dentistry, Okayama; and Department of Molecular Medicine, Sapporo Medical University, Sapporo, Japan

Search for other papers by Isao Date in
Current site
Google Scholar
PubMed Close
 M.D.
Page Range:
104–114
Volume/Issue:
Volume 103: Issue 1
DOI link:
https://doi.org/10.3171/jns.2005.103.1.0104
Restricted access

Purchase Now

USD  $45.00

JNS + Pediatrics - 1 year subscription bundle (Individuals Only)

USD  $525.00

JNS + Pediatrics + Spine - 1 year subscription bundle (Individuals Only)

USD  $624.00
Click here for subscription options

  • Purchase Now

    USD  $45.00

  • JNS + Pediatrics - 1 year subscription bundle (Individuals Only)

    USD  $525.00

  • JNS + Pediatrics + Spine - 1 year subscription bundle (Individuals Only)

    USD  $624.00
USD  $45.00
USD  $525.00
USD  $624.00
Print or Print + Online Sign in

Object

The authors evaluated the neuroprotective and angiogenic effects of a continuous and low-dose infusion of vascular endothelial growth factor (VEGF)-165 on cerebral ischemia in rats.

Methods

The authors introduced VEGF complementary (c)DNA into baby hamster kidney (BHK) cells and established a cell line that produces human VEGF165 (BHK-VEGF). The BHK-VEGF cells and BHK cells that had been transfected with an expression vector that did not contain human VEGF165 cDNA (BHK-control) were encapsulated. Both capsules were implanted into rat striata. Six days after capsule implantation, the right middle cerebral artery (MCA) was occluded. Some animals were killed 24 hours after occlusion to measure the volume of the resulting infarct and to perform immunohistochemical studies. Other animals were used for subsequent behavioral studies 1, 7, and 14 days after MCA occlusion.

The encapsulated BHK-VEGF cell grafts significantly reduced the volume of the infarct and the number of apoptotic cells in the penumbral area when compared with the effect of the BHK-control cell capsule. In addition, angiogenesis and gliogenesis significantly increased in the region around the capsule in animals that received BHK-VEGF cell capsules without an increase in focal cerebral blood flow; this did not occur in animals that received the BHK-control cell capsule. In behavioral studies rats that received the BHK-VEGF cell capsule displayed significant recovery while participating in the accelerating rotarod test after stroke.

Conclusions

Continuous intracerebral administration of low-dose VEGF165 through encapsulated grafts of VEGF-producing cells produces neuroprotective and angiogenic effects. These effects improve subsequent motor function.

  • Collapse
  • Expand

Contributor Notes

Address reprint requests to: Akimasa Yano, M.D., Department of Neurological Surgery, Okayama University Graduate School of Medicine and Dentistry, 2–5–1 Shikata-cho, Okayama 700–8558, Japan. email: a-yano@jd5.so-net.ne.jp.
  • 1.

    Aebischer P, , Tresco PA, , Winn SR, , Greene LA, & Jaeger CB: Long-term cross-species brain transplantation of a polymer-encapsulated dopamine-secreting cell line. Exp Neurol 111:269–275, 1991 Aebischer P, Tresco PA, Winn SR, Greene LA, Jaeger CB: Long-term cross-species brain transplantation of a polymer-encapsulated dopamine-secreting cell line. Exp Neurol 111:269–275, 1991

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 2.

    Bacic M, , Edwards NA, & Merrill MJ: Differential expression of vascular endothelial growth factor (vascular permeability factor) forms in rat tissues. Growth Factors 12:11–15, 1995 Bacic M, Edwards NA, Merrill MJ: Differential expression of vascular endothelial growth factor (vascular permeability factor) forms in rat tissues. Growth Factors 12:11–15, 1995

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 3.

    Banai S, , Jaklitsch MT, , Shou M, , Lazarous DF, , Scheinowitz M, & Biro S, et al: Angiogenic-induced enhancement of collateral blood flow to ischemic myocardium by vascular endothelial growth factor in dogs. Circulation 89:2183–2189, 1994 Banai S, Jaklitsch MT, Shou M, Lazarous DF, Scheinowitz M, Biro S, et al: Angiogenic-induced enhancement of collateral blood flow to ischemic myocardium by vascular endothelial growth factor in dogs. Circulation 89:2183–2189, 1994

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 4.

    Borlongan CV, & Sanberg PR: Elevated body swing test: a new behavioral parameter for rats with 6-hydroxydopamine-induced hemiparkinsonism. J Neurosci 15:5372–5378, 1995 Borlongan CV, Sanberg PR: Elevated body swing test: a new behavioral parameter for rats with 6-hydroxydopamine-induced hemiparkinsonism. J Neurosci 15:5372–5378, 1995

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 5.

    Charriaut-Marlangue C, , Margaill I, , Represa A, , Popovici T, , Plotkine M, & Ben-Ari Y: Apoptosis and necrosis after reversible focal ischemia: an in situ DNA fragmentation analysis. J Cereb Blood Flow Metab 16:186–194, 1996 Charriaut-Marlangue C, Margaill I, Represa A, Popovici T, Plotkine M, Ben-Ari Y: Apoptosis and necrosis after reversible focal ischemia: an in situ DNA fragmentation analysis. J Cereb Blood Flow Metab 16:186–194, 1996

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 6.

    Date I, , Shingo T, , Yoshida H, , Fujiwara K, , Kobayashi K, & Ohmoto T: Grafting of encapsulated dopamine-secreting cells in Parkinson's disease: long-term primate study. Cell Transplant 9:705–709, 2000 Date I, Shingo T, Yoshida H, Fujiwara K, Kobayashi K, Ohmoto T: Grafting of encapsulated dopamine-secreting cells in Parkinson's disease: long-term primate study. Cell Transplant 9:705–709, 2000

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 7.

    Dvorak HF, , Brown LF, , Detmar M, & Dvorak AM: Vascular permeability factor/vascular endothelial growth factor, microvascular hyperpermeability, and angiogenesis. Am J Pathol 146:1029–1039, 1995 Dvorak HF, Brown LF, Detmar M, Dvorak AM: Vascular permeability factor/vascular endothelial growth factor, microvascular hyperpermeability, and angiogenesis. Am J Pathol 146:1029–1039, 1995

    • Search Google Scholar
    • Export Citation
  • 8.

    Eddleston M, & Mucke L: Molecular profile of reactive astrocytes—implications for their role in neurologic disease. Neuroscience 54:15–36, 1993 Eddleston M, Mucke L: Molecular profile of reactive astrocytes—implications for their role in neurologic disease. Neuroscience 54:15–36, 1993

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 9.

    Ferrara N, & Davis-Smyth T: The biology of vascular endothelial growth factor. Endocr Rev 18:4–15, 1997 Ferrara N, Davis-Smyth T: The biology of vascular endothelial growth factor. Endocr Rev 18:4–15, 1997

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 10.

    Fujiwara K, , Date I, , Shingo T, , Yoshida H, , Kobayashi K, & Takeuchi A, et al: Reduction of infarct volume and apoptosis by grafting of encapsulated basic fibroblast growth factor-secreting cells in a model of middle cerebral artery occlusion in rats. J Neurosurg 99:1053–1062, 2003 Fujiwara K, Date I, Shingo T, Yoshida H, Kobayashi K, Takeuchi A, et al: Reduction of infarct volume and apoptosis by grafting of encapsulated basic fibroblast growth factor-secreting cells in a model of middle cerebral artery occlusion in rats. J Neurosurg 99:1053–1062, 2003

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 11.

    Gerber HP, , McMurtrey A, , Kowalski J, , Yan M, , Keyt BA, & Dixit V, 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 273:30336–30343, 1998 Gerber HP, McMurtrey A, Kowalski J, Yan M, Keyt BA, Dixit V, 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 273:30336–30343, 1998

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 12.

    Harrigan MR, , Ennis SR, , Masada T, & Keep RF: Intraventricular infusion of vascular endothelial growth factor promotes cerebral angiogenesis with minimal brain edema. Neurosurgery 50:589–598, 2002 Harrigan MR, Ennis SR, Masada T, Keep RF: Intraventricular infusion of vascular endothelial growth factor promotes cerebral angiogenesis with minimal brain edema. Neurosurgery 50:589–598, 2002

    • Search Google Scholar
    • Export Citation
  • 13.

    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 145:49–53, 2003 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 145:49–53, 2003

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 14.

    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 18:887–895, 1998 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 18:887–895, 1998

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 15.

    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 28:2039–2044, 1997 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 28:2039–2044, 1997

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 16.

    Hendel RC, , Henry TD, , Rocha-Singh K, , Isner JM, , Kereiakes DJ, & Giordano FJ, et al: Effect of intracoronary recombinant human vascular endothelial growth factor on myocardial perfusion: evidence for a dose-dependent effect. Circulation 101:118–121, 2000 Hendel RC, Henry TD, Rocha-Singh K, Isner JM, Kereiakes DJ, Giordano FJ, et al: Effect of intracoronary recombinant human vascular endothelial growth factor on myocardial perfusion: evidence for a dose-dependent effect. Circulation 101:118–121, 2000

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 17.

    Issa R, , Krupinski J, , Bujny T, , Kumar S, , Kaluza J, & Kumar P: Vascular endothelial growth factor and its receptor, KDR, in human brain tissue after ischemic stroke. Lab Invest 79:417–425, 1999 Issa R, Krupinski J, Bujny T, Kumar S, Kaluza J, Kumar P: Vascular endothelial growth factor and its receptor, KDR, in human brain tissue after ischemic stroke. Lab Invest 79:417–425, 1999

    • Search Google Scholar
    • Export Citation
  • 18.

    Jin K, , Zhu Y, , Sun Y, , Mao XO, , Xie L, & Greenberg DA: Vascular endothelial growth factor (VEGF) stimulates neurogenesis in vitro and in vivo. Proc Natl Acad Sci USA 99:11946–11950, 2002 Jin K, Zhu Y, Sun Y, Mao XO, Xie L, Greenberg DA: Vascular endothelial growth factor (VEGF) stimulates neurogenesis in vitro and in vivo. Proc Natl Acad Sci USA 99:11946–11950, 2002

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 19.

    Jin KL, , Mao XO, & Greenberg DA: Vascular endothelial growth factor: Direct neuroprotective effect in in vitro ischemia. Proc Natl Acad Sci USA 97:10242–10247, 2000 Jin KL, Mao XO, Greenberg DA: Vascular endothelial growth factor: Direct neuroprotective effect in in vitro ischemia. Proc Natl Acad Sci USA 97:10242–10247, 2000

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 20.

    Jin KL, , Mao XO, & Greenberg DA: Vascular endothelial growth factor rescues HN33 neural cells from death induced by serum withdrawal. J Mol Neurosci 14:197–203, 2000 Jin KL, Mao XO, Greenberg DA: Vascular endothelial growth factor rescues HN33 neural cells from death induced by serum withdrawal. J Mol Neurosci 14:197–203, 2000

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 21.

    Krum JM, , Mani N, & Rosenstein JM: Angiogenic and astroglial responses to vascular endothelial growth factor administration in adult rat brain. Neuroscience 110:589–604, 2002 Krum JM, Mani N, Rosenstein JM: Angiogenic and astroglial responses to vascular endothelial growth factor administration in adult rat brain. Neuroscience 110:589–604, 2002

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 22.

    Krum JM, & Rosenstein JM: Transient coexpression of nestin, GFAP, and vascular endothelial growth factor in mature reactive astroglia following neural grafting or brain wounds. Exp Neurol 160:348–360, 1999 Krum JM, Rosenstein JM: Transient coexpression of nestin, GFAP, and vascular endothelial growth factor in mature reactive astroglia following neural grafting or brain wounds. Exp Neurol 160:348–360, 1999

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 23.

    Lee MY, , Ju WK, , Cha JH, , Son BC, , Chun MH, & Kang JK, et al: Expression of vascular endothelial growth factor mRNA following transient forebrain ischemia in rats. Neurosci Lett 265:107–110, 1999 Lee MY, Ju WK, Cha JH, Son BC, Chun MH, Kang JK, et al: Expression of vascular endothelial growth factor mRNA following transient forebrain ischemia in rats. Neurosci Lett 265:107–110, 1999

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 24.

    Marti HJ, , Bernaudin M, , Bellail A, , Schoch H, , Euler M, & Petit E, et al: Hypoxia-induced vascular endothelial growth factor expression precedes neovascularization after cerebral ischemia. Am J Pathol 156:965–976, 2000 Marti HJ, Bernaudin M, Bellail A, Schoch H, Euler M, Petit E, et al: Hypoxia-induced vascular endothelial growth factor expression precedes neovascularization after cerebral ischemia. Am J Pathol 156:965–976, 2000

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 25.

    Matsuzaki H, , Tamatani M, , Yamaguchi A, , Namikawa K, , Kiyama H, & Vitek MP, et al: Vascular endothelial growth factor rescues hippocampal neurons from glutamate-induced toxicity: signal transduction cascades. FASEB J 15:1218–1220, 2001 Matsuzaki H, Tamatani M, Yamaguchi A, Namikawa K, Kiyama H, Vitek MP, et al: Vascular endothelial growth factor rescues hippocampal neurons from glutamate-induced toxicity: signal transduction cascades. FASEB J 15:1218–1220, 2001

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 26.

    Nakata N, , Kato H, & Kogure K: Protective effects of basic fibroblast growth factor against hippocampal neuronal damage following cerebral ischemia in the gerbil. Brain Res 605:354–356, 1993 Nakata N, Kato H, Kogure K: Protective effects of basic fibroblast growth factor against hippocampal neuronal damage following cerebral ischemia in the gerbil. Brain Res 605:354–356, 1993

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 27.

    Neufeld G, , Cohen T, , Gengrinovitch S, & Poltorak Z: Vascular endothelial growth factor (VEGF) and its receptors. FASEB J 13:9–22, 1999 Neufeld G, Cohen T, Gengrinovitch S, Poltorak Z: Vascular endothelial growth factor (VEGF) and its receptors. FASEB J 13:9–22, 1999

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 28.

    Niwa H, , Yamamura K, & Miyazaki J: Efficient selection for high-expression transfectants with a novel eukaryotic vector. Gene 108:193–199, 1991 Niwa H, Yamamura K, Miyazaki J: Efficient selection for high-expression transfectants with a novel eukaryotic vector. Gene 108:193–199, 1991

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 29.

    Oosthuyse B, , Moons L, , Storkebaum E, , Beck H, , Nuyens D, & Brusselmans K, et al: Deletion of the hypoxia-response element in the vascular endothelial growth factor promoter causes motor neuron degeneration. Nat Genet 28:131–138, 2001 Oosthuyse B, Moons L, Storkebaum E, Beck H, Nuyens D, Brusselmans K, et al: Deletion of the hypoxia-response element in the vascular endothelial growth factor promoter causes motor neuron degeneration. Nat Genet 28:131–138, 2001

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 30.

    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 58:654–666, 1999 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 58:654–666, 1999

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 31.

    Poltorak Z, , Cohen T, , Sivan R, , Kandelis Y, , Spira G, & Vlodavsky I, et al: VEGF145, a secreted vascular endothelial growth factor isoform that binds to extracellular matrix. J Biol Chem 272:7151–7158, 1997 Poltorak Z, Cohen T, Sivan R, Kandelis Y, Spira G, Vlodavsky I, et al: VEGF145, a secreted vascular endothelial growth factor isoform that binds to extracellular matrix. J Biol Chem 272:7151–7158, 1997

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 32.

    Proescholdt MA, , Heiss JD, , Walbridge S, , Muhlhauser J, , Capogrossi MC, & Oldfield EH, et al: Vascular endothelial growth factor (VEGF) modulates vascular permeability and inflammation in rat brain. J Neuropathol Exp Neurol 58:613–627, 1999 Proescholdt MA, Heiss JD, Walbridge S, Muhlhauser J, Capogrossi MC, Oldfield EH, et al: Vascular endothelial growth factor (VEGF) modulates vascular permeability and inflammation in rat brain. J Neuropathol Exp Neurol 58:613–627, 1999

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 33.

    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 95:7086–7091, 1998 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 95:7086–7091, 1998

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 34.

    Shingo T, , Date I, , Yoshida H, & Ohmoto T: Neuroprotective and restorative effects of intrastriatal grafting of encapsulated GDNF-producing cells in a rat model of Parkinson's disease. J Neurosci Res 69:946–954, 2002 Shingo T, Date I, Yoshida H, Ohmoto T: Neuroprotective and restorative effects of intrastriatal grafting of encapsulated GDNF-producing cells in a rat model of Parkinson's disease. J Neurosci Res 69:946–954, 2002

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 35.

    Silverman WF, , Krum JM, , Mani N, & Rosenstein JM: Vascular, glial and neuronal effects of vascular endothelial growth factor in mesencephalic explant cultures. Neuroscience 90:1529–1541, 1999 Silverman WF, Krum JM, Mani N, Rosenstein JM: Vascular, glial and neuronal effects of vascular endothelial growth factor in mesencephalic explant cultures. Neuroscience 90:1529–1541, 1999

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 36.

    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 19:5731–5740, 1999 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 19:5731–5740, 1999

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 37.

    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 111:1843–1851, 2003 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 111:1843–1851, 2003

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 38.

    Takeshita S, , Tsurumi Y, , Couffinahl T, , Asahara T, , Bauters C, & Symes J, et al: Gene transfer of naked DNA encoding for three isoforms of vascular endothelial growth factor stimulates collateral development in vivo. Lab Invest 75:487–501, 1996 Takeshita S, Tsurumi Y, Couffinahl T, Asahara T, Bauters C, Symes J, et al: Gene transfer of naked DNA encoding for three isoforms of vascular endothelial growth factor stimulates collateral development in vivo. Lab Invest 75:487–501, 1996

    • Search Google Scholar
    • Export Citation
  • 39.

    Takeshita S, , Zheng LP, , Brogi E, , Kearney M, , Pu LQ, & Bunting S, 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 93:662–670, 1994 Takeshita S, Zheng LP, Brogi E, Kearney M, Pu LQ, Bunting S, 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 93:662–670, 1994

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 40.

    van Bruggen N, , Thibodeaux H, , Palmer JT, , Lee WP, , Fu L, & Cairns B, et al: VEGF antagonism reduces edema formation and tissue damage after ischemia/reperfusion injury in the mouse brain. J Clin Invest 104:1613–1620, 1999 van Bruggen N, Thibodeaux H, Palmer JT, Lee WP, Fu L, Cairns B, et al: VEGF antagonism reduces edema formation and tissue damage after ischemia/reperfusion injury in the mouse brain. J Clin Invest 104:1613–1620, 1999

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 41.

    Wang Y, , Lin SZ, , Chiou AL, , Williams LR, & Hoffer BJ: Glial cell line-derived neurotrophic factor protects against ischemia-induced injury in the cerebral cortex. J Neurosci 17:4341–4348, 1997 Wang Y, Lin SZ, Chiou AL, Williams LR, Hoffer BJ: Glial cell line-derived neurotrophic factor protects against ischemia-induced injury in the cerebral cortex. J Neurosci 17:4341–4348, 1997

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 42.

    Yang K, & Cepko CL: Flk-1, a receptor for vascular endothelial growth factor (VEGF), is expressed by retinal progenitor cells. J Neurosci 16:6089–6099, 1996 Yang K, Cepko CL: Flk-1, a receptor for vascular endothelial growth factor (VEGF), is expressed by retinal progenitor cells. J Neurosci 16:6089–6099, 1996

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 43.

    Yao Y, , Kubota T, , Sato K, , Kitai R, , Takeuchi H, & Arishima H: Prognostic value of vascular endothelial growth factor and its receptors Flt-1 and Flk-1 in astrocytic tumours. Acta Neurochir 143:159–166, 2001 Yao Y, Kubota T, Sato K, Kitai R, Takeuchi H, Arishima H: Prognostic value of vascular endothelial growth factor and its receptors Flt-1 and Flk-1 in astrocytic tumours. Acta Neurochir 143:159–166, 2001

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 44.

    Yasuhara T, , Shingo T, , Kobayashi K, , Takeuchi A, , Yano A, & Muraoka K, et al: Neuroprotective effects of vascular endothelial growth factor (VEGF) on dopaminergic neurons in a rat model of Parkinson's disease. Eur J Neurosci 19:1494–1504, 2004 Yasuhara T, Shingo T, Kobayashi K, Takeuchi A, Yano A, Muraoka K, et al: Neuroprotective effects of vascular endothelial growth factor (VEGF) on dopaminergic neurons in a rat model of Parkinson's disease. Eur J Neurosci 19:1494–1504, 2004

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 45.

    Zhang ZG, , Zhang L, , Jiang Q, , Zhang R, , Davies K, & Powers C, et al: VEGF enhances angiogenesis and promotes blood-brain barrier leakage in the ischemic brain. J Clin Invest 106:829–838, 2000 Zhang ZG, Zhang L, Jiang Q, Zhang R, Davies K, Powers C, et al: VEGF enhances angiogenesis and promotes blood-brain barrier leakage in the ischemic brain. J Clin Invest 106:829–838, 2000

    • Crossref
    • Search Google Scholar
    • Export Citation

Metrics

All Time Past Year Past 30 Days
Abstract Views 899 230 2
Full Text Views 152 2 0
PDF Downloads 108 2 0
EPUB Downloads 0 0 0