Skip to main content

Advertisement

SpringerLink
Log in

Vascular endothelial growth factors (VEGFs) and stroke

  • Multi-author review
  • Published:
Cellular and Molecular Life Sciences Aims and scope Submit manuscript

Abstract

Vascular endothelial growth factors (VEGFs) have been shown to participate in atherosclerosis, arteriogenesis, cerebral edema, neuroprotection, neurogenesis, angiogenesis, postischemic brain and vessel repair, and the effects of transplanted stem cells in experimental stroke. Most of these actions involve VEGF-A and the VEGFR-2 receptor, but VEGF-B, placental growth factor, and VEGFR-1 have been implicated in some cases as well. VEGF signaling pathways represent important potential targets for the acute and chronic treatment of stroke.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Hirashima M (2009) Regulation of endothelial cell differentiation and arterial specification by VEGF and notch signaling. Anat Sci Int 84:95–101

    PubMed  CAS  Google Scholar 

  2. Shibuya M (2009) Brain angiogenesis in developmental and pathological processes: therapeutic aspects of vascular endothelial growth factor. FEBS J 276:4636–4643

    PubMed  CAS  Google Scholar 

  3. Schaper W (2009) Collateral circulation: past and present. Basic Res Cardiol 104:5–21

    PubMed  CAS  Google Scholar 

  4. Mackenzie F, Ruhrberg C (2012) Diverse roles for VEGF-A in the nervous system. Development 139:1371–1380

    PubMed  CAS  Google Scholar 

  5. Sluimer JC, Daemen MJ (2009) Novel concepts in atherogenesis: angiogenesis and hypoxia in atherosclerosis. J Pathol 218:7–29

    PubMed  Google Scholar 

  6. Yang GY, Yao JS, Huey M, Hashimoto T, Young WL (2004) Participation of PI3 K and ERK1/2 pathways are required for human brain vascular smooth muscle cell migration. Neurochem Int 44:441–446

    PubMed  CAS  Google Scholar 

  7. Hagberg CE, Falkevall A, Wang X, Larsson E, Huusko J, Nilsson I, van Meeteren LA, Samen E, Lu L, Vanwildemeersch M, Klar J, Genove G, Pietras K, Stone-Elander S, Claesson-Welsh L, Yla-Herttuala S, Lindahl P, Eriksson U (2010) Vascular endothelial growth factor B controls endothelial fatty acid uptake. Nature 464:917–921

    PubMed  CAS  Google Scholar 

  8. Hiyama T, Tanaka T, Endo S, Komine K, Kudo T, Kobayashi H, Shiokawa Y (2010) Angiogenesis in atherosclerotic plaque obtained from carotid endarterectomy: association between symptomatology and plaque morphology. Neurol Med Chir (Tokyo) 50:1056–1061

    Google Scholar 

  9. Petrovan RJ, Kaplan CD, Reisfeld RA, Curtiss LK (2007) DNA vaccination against VEGF receptor 2 reduces atherosclerosis in LDL receptor-deficient mice. Arterioscler Thromb Vasc Biol 27:1095–1100

    PubMed  CAS  Google Scholar 

  10. Wang Y, Zhou Y, He L, Hong K, Su H, Wu Y, Wu Q, Han M, Cheng X (2011) Gene delivery of soluble vascular endothelial growth factor receptor-1 (sFlt-1) inhibits intra-plaque angiogenesis and suppresses development of atherosclerotic plaque. Clin Exp Med 11:113–121

    PubMed  Google Scholar 

  11. Bang OY, Saver JL, Buck BH, Alger JR, Starkman S, Ovbiagele B, Kim D, Jahan R, Duckwiler GR, Yoon SR, Vinuela F, Liebeskind DS (2008) Impact of collateral flow on tissue fate in acute ischaemic stroke. J Neurol Neurosurg Psychiatry 79:625–629

    PubMed  CAS  Google Scholar 

  12. Coyle P, Heistad DD (1991) Development of collaterals in the cerebral circulation. Blood Vessels 28:183–189

    PubMed  CAS  Google Scholar 

  13. Busch HJ, Buschmann IR, Mies G, Bode C, Hossmann KA (2003) Arteriogenesis in hypoperfused rat brain. J Cereb Blood Flow Metab 23:621–628

    PubMed  Google Scholar 

  14. Buschmann IR, Busch HJ, Mies G, Hossmann KA (2003) Therapeutic induction of arteriogenesis in hypoperfused rat brain via granulocyte-macrophage colony-stimulating factor. Circulation 108:610–615

    PubMed  CAS  Google Scholar 

  15. Toyota E, Warltier DC, Brock T, Ritman E, Kolz C, O’Malley P, Rocic P, Focardi M, Chilian WM (2005) Vascular endothelial growth factor is required for coronary collateral growth in the rat. Circulation 112:2108–2113

    PubMed  CAS  Google Scholar 

  16. Clayton JA, Chalothorn D, Faber JE (2008) Vascular endothelial growth factor-A specifies formation of native collaterals and regulates collateral growth in ischemia. Circ Res 103:1027–1036

    PubMed  CAS  Google Scholar 

  17. Kovacs Z, Ikezaki K, Samoto K, Inamura T, Fukui M (1996) VEGF and flt: expression time kinetics in rat brain infarct. Stroke 27:1865–1873

    PubMed  CAS  Google Scholar 

  18. Hayashi T, Abe K, Suzuki H, Itomaya Y (1997) Rapid induction of vascular endothelial growth factor gene expression after transient middle cerebral artery occlusion in rats. Stroke 28:2039–2044

    PubMed  CAS  Google Scholar 

  19. Lennmyr F, Ata KA, Funa K, Olsson Y, Terent A (1998) 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 57:874–882

    PubMed  CAS  Google Scholar 

  20. Cobbs CS, Chen J, Greenberg DA, Graham SH (1998) Vascular endothelial growth factor expression in rat focal cerebral ischemia. Neurosci Lett 249:79–82

    PubMed  CAS  Google Scholar 

  21. Plate KH, Beck H, Danner S, Allegrini PR, Wiessner C (1999) Cell type specific upregulation of vascular endothelial growth factor in an MCA-occlusion model of cerebral infarct. J Neuropathol Exp Neurol 58:654–666

    PubMed  CAS  Google Scholar 

  22. Mu D, Jiang X, Sheldon RA, Fox CK, Hamrick SE, Vexler ZS, Ferriero DM (2003) Regulation of hypoxia-inducible factor 1alpha and induction of vascular endothelial growth factor in a rat neonatal stroke model. Neurobiol Disease 14:524–534

    CAS  Google Scholar 

  23. Gu W, Brannstrom T, Jiang W, Bergh A, Wester P (2001) Vascular endothelial growth factor-A and -C protein up-regulation and early angiogenesis in a rat photothrombotic ring stroke model with spontaneous reperfusion. Acta Neuropathol (Berl) 102:216–226

    CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  25. Jin KL, Mao XO, Nagayama T, Goldsmith PC, Greenberg DA (2000) Induction of vascular endothelial growth factor and hypoxia-inducible factor-1alpha by global ischemia in rat brain. Neuroscience 99:577–585

    PubMed  CAS  Google Scholar 

  26. Jin KL, Mao XO, Nagayama T, Goldsmith PC, Greenberg DA (2000) Induction of vascular endothelial growth factor receptors and phosphatidylinositol 3′-kinase/Akt signaling by global cerebral ischemia in the rat. Neuroscience 100:713–717

    PubMed  CAS  Google Scholar 

  27. Leung DW, Cachianes G, Kuang W-J, Goeddel DV, Ferrara N (1989) Vascular endothelial growth factor is a secreted angiogenic mitogen. Science 246:1306–1309

    PubMed  CAS  Google Scholar 

  28. Keck PJ, Hauser SD, Krivi G, Sanzo K, Warren T, Feder J, Connolly DT (1989) Vascular permeability factor, an endothelial cell mitogen related to PDGF. Science 246:1309–1312

    PubMed  CAS  Google Scholar 

  29. Weis SM, Cheresh DA (2005) Pathophysiological consequences of VEGF-induced vascular permeability. Nature 437:497–504

    PubMed  CAS  Google Scholar 

  30. 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 (1999) VEGF antagonism reduces edema formation and tissue damage after ischemia/reperfusion injury in the mouse brain. J Clin Invest 104:1613–1620

    PubMed  Google Scholar 

  31. Zhang ZG, Zhang L, Jiang Q, Zhang R, Davies K, Powers C, Bruggen N, Chopp M (2000) VEGF enhances angiogenesis and promotes blood–brain barrier leakage in the ischemic brain. J Clin Invest 106:829–838

    PubMed  CAS  Google Scholar 

  32. Kimura R, Nakase H, Tamaki R, Sakaki T (2005) Vascular endothelial growth factor antagonist reduces brain edema formation and venous infarction. Stroke 36:1259–1263

    PubMed  CAS  Google Scholar 

  33. Zhang ZG, Zhang L, Croll SD, Chopp M (2002) Angiopoietin-1 reduces cerebral blood vessel leakage and ischemic lesion volume after focal cerebral embolic ischemia in mice. Neuroscience 113:683–687

    PubMed  CAS  Google Scholar 

  34. Greenberg DA, Jin K (2005) From angiogenesis to neuropathology. Nature 438:954–959

    PubMed  CAS  Google Scholar 

  35. Sondell M, Sundler F, Kanje M (2000) Vascular endothelial growth factor is a neurotrophic factor which stimulates axonal outgrowth through the flk-1 receptor. Eur J Neurosci 12:4243–4254

    PubMed  CAS  Google Scholar 

  36. Sondell M, Lundborg G, Kanje M (1999) 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

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  39. Ogunshola OO, Antic A, Donoghue MJ, Fan S-Y, Kim H, Stewart WB, Madri JA, Ment LR (2002) Paracrine and autocrine functions of neuronal vascular endothelial growth factor (VEGF) in the central nervous system. J Biol Chem 277:11410–11415

    PubMed  CAS  Google Scholar 

  40. Rosenstein JM, Mani N, Khaibullina A, Krum JM (2003) Neurotrophic effects of vascular endothelial growth factor on organotypic cortical explants and primary cortical neurons. J Neurosci 23:11036–11044

    PubMed  CAS  Google Scholar 

  41. Khaibullina AA, Rosenstein JM, Krum JM (2004) Vascular endothelial growth factor promotes neurite maturation in primary CNS neuronal cultures. Dev Brain Res 148:59–68

    CAS  Google Scholar 

  42. Jin K, Mao XO, Greenberg DA (2006) Vascular endothelial growth factor stimulates neurite outgrowth from cerebral cortical neurons via Rho kinase signaling. J Neurobiol 66:236–242

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  45. Svensson B, Peters M, Konig HG, Poppe M, Levkau B, Rothermundt M, Arolt V, Kogel D, Prehn JH (2002) Vascular endothelial growth factor protects cultured rat hippocampal neurons against hypoxic injury via an antiexcitotoxic, caspase-independent mechanism. J Cereb Blood Flow Metab 22:1170–1175

    PubMed  CAS  Google Scholar 

  46. Wick A, Wick W, Waltenberger J, Weller M, Dichgans J, Schulz JB (2002) Neuroprotection by hypoxic preconditioning requires sequential activation of vascular endothelial growth factor receptor and Akt. J Neurosci 22:6401–6407

    PubMed  CAS  Google Scholar 

  47. Du H, Li P, Pan Y, Li W, Hou J, Chen H, Wang J, Tang H (2010) Vascular endothelial growth factor signaling implicated in neuroprotective effects of placental growth factor in an in vitro ischemic model. Brain Res 1357:1–8

    PubMed  CAS  Google Scholar 

  48. Hayashi T, Abe K, Itoyama Y (1998) 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

    PubMed  CAS  Google Scholar 

  49. Bao WL, Lu SD, Wang H, Sun FY (1999) Intraventricular vascular endothelial growth factor antibody increases infarct volume following transient cerebral ischemia. Chung Kuo Yao Li Hsueh Pao 20:313–318

    PubMed  CAS  Google Scholar 

  50. Sun Y, Jin K, Xie L, Childs J, Mao XO, Logvinova A, Greenberg DA (2003) VEGF-induced neuroprotection, neurogenesis, and angiogenesis after focal cerebral ischemia. J Clin Invest 111:1843–1851

    PubMed  CAS  Google Scholar 

  51. Wang Y, Galvan V, Gorostiza O, Ataie M, Jin K, Greenberg DA (2006) Vascular endothelial growth factor improves recovery of sensorimotor and cognitive deficits after focal cerebral ischemia in the rat. Brain Res 1115:186–193

    PubMed  CAS  Google Scholar 

  52. Wang Y, Kilic E, Kilic U, Weber B, Bassetti CL, Marti HH, Hermann DM (2005) VEGF overexpression induces post-ischaemic neuroprotection, but facilitates haemodynamic steal phenomena. Brain 128:52–63

    PubMed  Google Scholar 

  53. Kaya D, Gursoy-Ozdemir Y, Yemisci M, Tuncer N, Aktan S, Dalkara T (2005) VEGF protects brain against focal ischemia without increasing blood–brain permeability when administered intracerebroventricularly. J Cereb Blood Flow Metab 25:1111–1118

    PubMed  CAS  Google Scholar 

  54. Feng Y, Rhodes PG, Bhatt AJ (2008) Neuroprotective effects of vascular endothelial growth factor following hypoxic ischemic brain injury in neonatal rats. Pediatr Res 64:370–374

    PubMed  CAS  Google Scholar 

  55. Zheng XR, Zhang SS, Yang YJ, Yin F, Wang X, Zhong L, Yu XH (2010) Adenoviral vector-mediated transduction of VEGF improves neural functional recovery after hypoxia-ischemic brain damage in neonatal rats. Brain Res Bull 81:372–377

    PubMed  CAS  Google Scholar 

  56. Shimotake J, Derugin N, Wendland M, Vexler ZS, Ferriero DM (2010) Vascular endothelial growth factor receptor-2 inhibition promotes cell death and limits endothelial cell proliferation in a neonatal rodent model of stroke. Stroke 41:343–349

    PubMed  CAS  Google Scholar 

  57. Sun Y, Jin K, Childs JT, Xie L, Mao XO, Greenberg DA (2004) Increased severity of cerebral ischemic injury in vascular endothelial growth factor-B-deficient mice. J Cereb Blood Flow Metab 24:1146–1152

    PubMed  CAS  Google Scholar 

  58. Mould AW, Greco SA, Cahill MM, Tonks ID, Bellomo D, Patterson C, Zournazi A, Nash A, Scotney P, Hayward NK, Kay GF (2005) Transgenic overexpression of vascular endothelial growth factor-B isoforms by endothelial cells potentiates postnatal vessel growth in vivo and in vitro. Circ Res 97:e60–e70

    PubMed  CAS  Google Scholar 

  59. Sawano A, Takahashi T, Yamaguchi S, Aonuma M, Shibuya M (1996) Flt-1 but not KDR/Flk-1 tyrosine kinase is a receptor for placenta growth factor, which is related to vascular endothelial growth factor. Cell Growth Diff 7:213–221

    PubMed  CAS  Google Scholar 

  60. Gu W, Brannstrom T, Wester P (2000) Cortical neurogenesis in adult rats after reversible photothrombotic stroke. J Cereb Blood Flow Metab 20:1166–1173

    PubMed  CAS  Google Scholar 

  61. Jin K, Minami M, Lan JQ, Mao XO, Batteur S, Simon RP, Greenberg DA (2001) Neurogenesis in dentate subgranular zone and rostral subventricular zone after focal cerebral ischemia in the rat. Proc Natl Acad Sci USA 98:4710–4715

    PubMed  CAS  Google Scholar 

  62. Zhang RL, Zhang ZG, Zhang L, Chopp M (2001) Proliferation and differentiation of progenitor cells in the cortex and the subventricular zone in the adult rat after focal cerebral ischemia. Neuroscience 105:33–41

    PubMed  CAS  Google Scholar 

  63. Arvidsson A, Collin T, Kirik D, Kokaia Z, Lindvall O (2002) Neuronal replacement from endogenous precursors in the adult brain after stroke. Nat Med 8:963–970

    PubMed  CAS  Google Scholar 

  64. Parent JM, Vexler ZS, Gong C, Derugin N, Ferriero DM (2002) Rat forebrain neurogenesis and striatal neuron replacement after focal stroke. Ann Neurol 52:802–813

    PubMed  Google Scholar 

  65. Jin K, Wang X, Xie L, Mao XO, Zhu W, Wang Y, Shen J, Mao Y, Banwait S, Greenberg DA (2006) Evidence for stroke-induced neurogenesis in the human brain. Proc Natl Acad Sci USA 103:13198–13202

    PubMed  CAS  Google Scholar 

  66. Minger SL, Ekonomou A, Carta EM, Chinoy A, Perry RH, Ballard CG (2007) Endogenous neurogenesis in the human brain following cerebral infarction. Regen Med 2:69–74

    PubMed  Google Scholar 

  67. Jin K, Sun Y, Xie L, Peel A, Mao XO, Batteur S, Greenberg DA (2003) Directed migration of neuronal precursors into the ischemic cerebral cortex and striatum. Mol Cell Neurosci 24:171–189

    PubMed  CAS  Google Scholar 

  68. Zhang R, Zhang Z, Wang L, Wang Y, Gousev A, Zhang L, Ho KL, Morshead C, Chopp M (2004) Activated neural stem cells contribute to stroke-induced neurogenesis and neuroblast migration toward the infarct boundary in adult rats. J Cereb Blood Flow Metab 24:441–448

    PubMed  Google Scholar 

  69. Raber J, Fan Y, Matsumori Y, Liu Z, Weinstein PR, Fike JR, Liu J (2004) Irradiation attenuates neurogenesis and exacerbates ischemia-induced deficits. Ann Neurol 55:381–389

    PubMed  Google Scholar 

  70. Jin K, Wang X, Xie L, Mao XO, Greenberg DA (2010) Transgenic ablation of doublecortin-expressing cells suppresses adult neurogenesis and worsens stroke outcome in mice. Proc Natl Acad Sci USA 107:7993–7998

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  72. Chen J, Zacharek A, Li A, Zhang C, Ding J, Roberts C, Lu M, Kapke A, Chopp M (2006) Vascular endothelial growth factor mediates atorvastatin-induced mammalian achaete-scute homologue-1 gene expression and neuronal differentiation after stroke in retired breeder rats. Neuroscience 141:737–744

    PubMed  CAS  Google Scholar 

  73. Warner-Schmidt JL, Duman RS (2007) VEGF is an essential mediator of the neurogenic and behavioral actions of antidepressants. Proc Natl Acad Sci USA 104:4647–4652

    PubMed  CAS  Google Scholar 

  74. Sun Y, Jin K, Childs JT, Xie L, Mao XO, Greenberg DA (2006) Vascular endothelial growth factor-B (VEGFB) stimulates neurogenesis: evidence from knockout mice and growth factor administration. Dev Biol 289:329–335

    PubMed  CAS  Google Scholar 

  75. Plate KH (1999) Mechanisms of angiogenesis in the brain. J Neuropathol Exp Neurol 58:313–320

    PubMed  CAS  Google Scholar 

  76. Chen HH, Chien CH, Liu HM (1994) Correlation between angiogenesis and basic fibroblast growth factor expression in experimental brain infarct. Stroke 25:1651–1657

    PubMed  CAS  Google Scholar 

  77. Liu HM (1988) Neovasculature and blood-brain barrier in ischemic brain infarct. Acta Neuropathol 75:422–426

    PubMed  CAS  Google Scholar 

  78. Krupinski J, Kaluza J, Kumar P, Kumar S, Wang JM (1994) Role of angiogenesis in patients with cerebral ischemic stroke. Stroke 25:1794–1798

    PubMed  CAS  Google Scholar 

  79. Abumiya T, Lucero J, Heo JH, Tagaya M, Koziol JA, Copeland BR, del Zoppo GJ (1999) Activated microvessels express vascular endothelial growth factor and integrin alpha(v)beta3 during focal cerebral ischemia. J Cereb Blood Flow Metab 19:1038–1050

    PubMed  CAS  Google Scholar 

  80. Zhang ZG, Zhang L, Tsang W, Soltanian-Zadeh H, Morris D, Zhang R, Goussev A, Powers C, Yeich T, Chopp M (2002) Correlation of VEGF and angiopoietin expression with disruption of blood-brain barrier and angiogenesis after focal cerebral ischemia. J Cereb Blood Flow Metab 22:379–392

    PubMed  CAS  Google Scholar 

  81. Zhang R, Wang L, Zhang L, Chen J, Zhu Z, Zhang Z, Chopp M (2003) Nitric oxide enhances angiogenesis via the synthesis of vascular endothelial growth factor and cGMP after stroke in rat. Circ Res 92:308–313

    PubMed  CAS  Google Scholar 

  82. Freitas-Andrade M, Carmeliet P, Charlebois C, Stanimirovic DB, Moreno MJ (2012) PlGF knockout delays brain vessel growth and maturation upon systemic hypoxic challenge. J Cereb Blood Flow Metab 32:663–675

    PubMed  CAS  Google Scholar 

  83. Carmichael ST (2006) Cellular and molecular mechanisms of neural repair after stroke: making waves. Ann Neurol 59:735–742

    PubMed  CAS  Google Scholar 

  84. Nudo RJ (2007) Postinfarct cortical plasticity and behavioral recovery. Stroke 38:840–845

    PubMed  Google Scholar 

  85. Carmichael ST, Archibeque I, Luke L, Nolan T, Momiy J, Li S (2005) Growth-associated gene expression after stroke: evidence for a growth-promoting region in peri-infarct cortex. Exp Neurol 193:291–311

    PubMed  CAS  Google Scholar 

  86. Reinecke S, Lutzenburg M, Hagemann G, Bruehl C, Neumann-Haefelin T, Witte OW (1999) Electrophysiological transcortical diaschisis after middle cerebral artery occlusion (MCAO) in rats. Neurosci Lett 261:85–88

    PubMed  CAS  Google Scholar 

  87. Stroemer RP, Kent TA, Hulsebosch CE (1995) Neocortical neural sprouting, synaptogenesis, and behavioral recovery after neocortical infarction in rats. Stroke 26:2135–2144

    PubMed  CAS  Google Scholar 

  88. Frost SB, Barbay S, Friel KM, Plautz EJ, Nudo RJ (2003) Reorganization of remote cortical regions after ischemic brain injury: a potential substrate for stroke recovery. J Neurophysiol 89:3205–3214

    PubMed  CAS  Google Scholar 

  89. Carmichael ST, Wei L, Rovainen CM, Woolsey TA (2001) New patterns of intracortical projections after focal cortical stroke. Neurobiol Disease 8:910–922

    CAS  Google Scholar 

  90. Dancause N, Barbay S, Frost SB, Plautz EJ, Chen D, Zoubina EV, Stowe AM, Nudo RJ (2005) Extensive cortical rewiring after brain injury. J Neurosci 25:10167–10179

    PubMed  CAS  Google Scholar 

  91. Stowe AM, Plautz EJ, Eisner-Janowicz I, Frost SB, Barbay S, Zoubina EV, Dancause N, Taylor MD, Nudo RJ (2007) VEGF protein associates to neurons in remote regions following cortical infarct. J Cereb Blood Flow Metab 27:76–85

    PubMed  CAS  Google Scholar 

  92. Stowe AMPE, Nguyen P, Frost SB, Eisner-Janowicz I, Barbay S, Dancause N, Sensarma A, Taylor MD, Zoubina EV, Nudo RJ (2008) Neuronal HIF-1α protein and VEGFR-2 immunoreactivity in functionally related motor areas following a focal M1 infarct. J Cereb Blood Flow Metab 28:612–620

    PubMed  CAS  Google Scholar 

  93. Watt SM, Athanassopoulos A, Harris AL, Tsaknakis G (2010) Human endothelial stem/progenitor cells, angiogenic factors and vascular repair. J R Soc Interface 7(Suppl 6):S731–S751

    PubMed  Google Scholar 

  94. Kalka C, Masuda H, Takahashi T, Gordon R, Tepper O, Gravereaux E, Pieczek A, Iwaguro H, Hayashi SI, Isner JM, Asahara T (2000) Vascular endothelial growth factor165 gene transfer augments circulating endothelial progenitor cells in human subjects. Circ Res 86:1198–1202

    PubMed  CAS  Google Scholar 

  95. Kalka C, Tehrani H, Laudenberg B, Vale PR, Isner JM, Asahara T, Symes JF (2000) VEGF gene transfer mobilizes endothelial progenitor cells in patients with inoperable coronary disease. Ann Thorac Surg 70:829–834

    PubMed  CAS  Google Scholar 

  96. Li B, Sharpe EE, Maupin AB, Teleron AA, Pyle AL, Carmeliet P, Young PP (2006) VEGF and PlGF promote adult vasculogenesis by enhancing EPC recruitment and vessel formation at the site of tumor neovascularization. FASEB J 20:1495–1497

    PubMed  CAS  Google Scholar 

  97. Ghani U, Shuaib A, Salam A, Nasir A, Shuaib U, Jeerakathil T, Sher F, O’Rourke F, Nasser AM, Schwindt B, Todd K (2005) Endothelial progenitor cells during cerebrovascular disease. Stroke 36:151–153

    PubMed  Google Scholar 

  98. Sobrino T, Hurtado O, Moro MA, Rodriguez-Yanez M, Castellanos M, Brea D, Moldes O, Blanco M, Arenillas JF, Leira R, Davalos A, Lizasoain I, Castillo J (2007) The increase of circulating endothelial progenitor cells after acute ischemic stroke is associated with good outcome. Stroke 38:2759–2764

    PubMed  Google Scholar 

  99. Sobrino T, Perez-Mato M, Brea D, Rodriguez-Yanez M, Blanco M, Castillo J (2012) Temporal profile of molecular signatures associated with circulating endothelial progenitor cells in human ischemic stroke. J Neurosci Res 90:1788–1793

    PubMed  CAS  Google Scholar 

  100. Chu K, Park KI, Lee ST, Jung KH, Ko SY, Kang L, Sinn DI, Lee YS, Kim SU, Kim M, Roh JK (2005) Combined treatment of vascular endothelial growth factor and human neural stem cells in experimental focal cerebral ischemia. Neurosci Res 53:384–390

    PubMed  CAS  Google Scholar 

  101. Zhu W, Mao Y, Zhao Y, Zhou LF, Wang Y, Zhu JH, Zhu Y, Yang GY (2005) Transplantation of vascular endothelial growth factor-transfected neural stem cells into the rat brain provides neuroprotection after transient focal cerebral ischemia. Neurosurgery 57:325–333

    PubMed  Google Scholar 

  102. Lee HJ, Kim KS, Park IH, Kim SU (2007) Human neural stem cells over-expressing VEGF provide neuroprotection, angiogenesis and functional recovery in mouse stroke model. PLoS ONE 2:e156

    PubMed  Google Scholar 

  103. Liu H, Honmou O, Harada K, Nakamura K, Houkin K, Hamada H, Kocsis JD (2006) Neuroprotection by PlGF gene-modified human mesenchymal stem cells after cerebral ischaemia. Brain 129:2734–2745

    PubMed  CAS  Google Scholar 

  104. Harms KM, Li L, Cunningham LA (2010) Murine neural stem/progenitor cells protect neurons against ischemia by HIF-1alpha-regulated VEGF signaling. PLoS ONE 5:e9767

    PubMed  Google Scholar 

  105. Horie N, Pereira MP, Niizuma K, Sun G, Keren-Gill H, Encarnacion A, Shamloo M, Hamilton SA, Jiang K, Huhn S, Palmer TD, Bliss TM, Steinberg GK (2011) Transplanted stem cell-secreted vascular endothelial growth factor effects poststroke recovery, inflammation, and vascular repair. Stem Cells 29:274–285

    PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This study was supported by National Institutes of Health grant R01 NS44921.

Author information

Authors and Affiliations

  1. Buck Institute for Research on Aging, Novato, CA, 94945, USA

    David A. Greenberg & Kunlin Jin

  2. Department of Pharmacology and Neuroscience, University of North Texas Health Science Center, Fort Worth, TX, 76107, USA

    Kunlin Jin

Authors
  1. David A. Greenberg
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Kunlin Jin
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to David A. Greenberg.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Greenberg, D.A., Jin, K. Vascular endothelial growth factors (VEGFs) and stroke. Cell. Mol. Life Sci. 70, 1753–1761 (2013). https://doi.org/10.1007/s00018-013-1282-8

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00018-013-1282-8

Keywords

Search

Navigation