Neurochemical Research

, Volume 32, Issue 12, pp 2032–2045 | Cite as

Cell–cell Signaling in the Neurovascular Unit

  • Josephine Lok
  • Punkaj Gupta
  • Shuzhen Guo
  • Woo Jean Kim
  • Michael J. Whalen
  • Klaus van Leyen
  • Eng H. Lo
Original Paper


Historically, the neuron has been the conceptual focus for almost all of neuroscience research. In recent years, however, the concept of the neurovascular unit has emerged as a new paradigm for investigating both physiology and pathology in the CNS. This concept proposes that a purely neurocentric focus is not sufficient, and emphasizes that all cell types in the brain including neuronal, glial and vascular components, must be examined in an integrated context. Cell–cell signaling and coupling between these different compartments form the basis for normal function. Disordered signaling and perturbed coupling form the basis for dysfunction and disease. In this mini-review, we will survey four examples of this phenomenon: hemodynamic neurovascular coupling linking blood flow to brain activity; cellular communications that evoke the blood–brain barrier phenotype; parallel systems that underlie both neurogenesis and angiogenesis in the CNS; and finally, the potential exchange of trophic factors that may link neuronal, glial and vascular homeostasis.


Neurodegeneration Stroke Blood–brain barrier Neurogenesis Angiogenesis Neuroprotection 



Funded in part by NIH grants R01-NS37074, R01-NS40529, R01-NS48422, R01-NS53560, R01-NS56458, R01-NS47447, P50-NS10828, P01-NS55104, and a Bugher award from the American Heart Association. Many of the ideas presented here come from many leaders in the field. Key concepts were derived from seminal reviews in the area, especially the following: Abbott, N.J. et al, J of Biochemistry and Molecular Biology 2006; Carmeliet, P., Nature Reviews Genetics 2003 ; Drake, C.T. et al, Brain and Language 2006; Kim, J.H. et al, J of Biochemistry and Molecular Biology 2006; Iadecola, C., Nature Reviews Neuroscience 2004; Park, J.A. et al, Biochem Biophys Res Commun 2003; Pelligrino, D.A., J. Appl Physiol 2006; Ward, N.L. et al, Neurological Research 2004. We apologize to our many colleagues whose work we could not directly acknowledge due to space limitations.


  1. 1.
    Abbott NJ, Ronnback L, Hansson E (2006) Astrocyte-endothelial interactions at the blood–brain barrier. Nat Rev Neurosci 7:41–53PubMedGoogle Scholar
  2. 2.
    Iadecola C (2004) Neurovascular regulation in the normal brain and in Alzheimer’s disease. Nat Rev Neurosci 5:347–360PubMedGoogle Scholar
  3. 3.
    Park JA, Choi KS, Kim SY, Kim KW (2003) Coordinated interaction of the vascular and nervous systems: from molecule- to cell-based approaches. Biochem Biophys Res Commun 311:247–253PubMedGoogle Scholar
  4. 4.
    Allan S (2006) The neurovascular unit and the key role of astrocytes in the regulation of cerebral blood flow. Cerebrovasc Dis 21:137–138PubMedGoogle Scholar
  5. 5.
    Hawkins BT, Davis TP (2005) The blood–brain barrier/neurovascular unit in health and disease. Pharmacol Rev 57:173–185PubMedGoogle Scholar
  6. 6.
    Lo EH, Broderick JP, Moskowitz MA (2004) tPA and proteolysis in the neurovascular unit. Stroke 35:354–356PubMedGoogle Scholar
  7. 7.
    Drake CT, Iadecola C (2006) The role of neuronal signaling in controlling cerebral blood flow. Brain Lang, doi:10.1016/j.bandl.2006.08.002Google Scholar
  8. 8.
    Lassen NA, Larsen B (1980) Cortical activity in the left and right hemispheres during language-related brain functions. Phonetica 37:27–37PubMedCrossRefGoogle Scholar
  9. 9.
    Foit A, Larsen B, Hattori S, Skinhoj E, Lassen NA (1980) Cortical activation during somatosensory stimulation and voluntary movement in man: a regional cerebral blood flow study. Electroencephalogr Clin Neurophysiol 50:426–436PubMedGoogle Scholar
  10. 10.
    Hougaard K, Oikawa T, Sveinsdottir E, Skinoj E, Ingvar DH, Lassen NA (1976) Regional cerebral blood flow in focal cortical epilepsy. Arch Neurol 33:527–535PubMedGoogle Scholar
  11. 11.
    Jones EG (1970) On the mode of entry of blood vessels into the cerebral cortex. J Anat 106:507–520PubMedGoogle Scholar
  12. 12.
    Edvinsson L, Hamel E (2002) Perivascular nerves in brain vessels. In: Edvinsson L, Krause DN (eds) Cerebral blood flow and metabolism. Lippincott, Williams and Wilkins, Philadelphia, pp 43–67Google Scholar
  13. 13.
    Iadecola C (1998) Cerebral circulatory dysregulation in ischemia. In: Ginsberg D, Bogousslavsky J (eds) Cerebrovascular diseases. Blackwell Science, Cambridge, MA, pp 319–322Google Scholar
  14. 14.
    Takano T, Tian GF, Peng W, Lou N, Libionka W, Han X, Nedergaard M (2006) Astrocyte-mediated control of cerebral blood flow. Nat Neurosci 9:260–267PubMedGoogle Scholar
  15. 15.
    Cohen Z, Bonvento G, Lacombe P, Hamel E (1996) Serotonin in the regulation of brain microcirculation. Prog Neurobiol 50:335–362PubMedGoogle Scholar
  16. 16.
    Rennels ML, Nelson E (1975) Capillary innervation in the mammalian central nervous system: an electron microscopic demonstration. Am J Anat 144:233–241PubMedGoogle Scholar
  17. 17.
    Maynard EA, Schultz RL, Pease DC (1957) Electron microscopy of the vascular bed of rat cerebral cortex. Am J Anat 100:409–433PubMedGoogle Scholar
  18. 18.
    Hirase H (2005) A multi-photon window onto neuronal-glial-vascular communication. Trends Neurosci 28:217–219PubMedGoogle Scholar
  19. 19.
    Mulligan SJ, MacVicar BA (2004) Calcium transients in astrocyte endfeet cause cerebrovascular constrictions. Nature 431:195–199PubMedGoogle Scholar
  20. 20.
    Zonta M, Sebelin A, Gobbo S, Fellin T, Pozzan T, Carmignoto G (2003) Glutamate-mediated cytosolic calcium oscillations regulate a pulsatile prostaglandin release from cultured rat astrocytes. J Physiol 553:407–414PubMedGoogle Scholar
  21. 21.
    Busija DW (1993) Cerebral autoregulation. In: Philis JW (ed) The regulation of cerebral blood flow. CRC Press, Boca Raton, pp 45–64Google Scholar
  22. 22.
    Fergus A, Lee KS (1997) GABAergic regulation of cerebral microvascular tone in the rat. J Cereb Blood Flow Metab 17:992–1003PubMedGoogle Scholar
  23. 23.
    Iadecola C (1998) Neurogenic control of the cerebral microcirculation: is dopamine minding the store? Nat Neurosci 1:263–265PubMedGoogle Scholar
  24. 24.
    Uddman R, Edvinsson L (1989) Neuropeptides in the cerebral circulation. Cerebrovasc Brain Metab Rev 1:230–252PubMedGoogle Scholar
  25. 25.
    Bhardwaj A, Northington FJ, Carhuapoma JR, Falck JR, Harder DR, Traystman RJ, Koehler RC (2000) P-450 epoxygenase and NO synthase inhibitors reduce cerebral blood flow response to N-methyl-d-aspartate. Am J Physiol Heart Circ Physiol 279: H1616–H1624PubMedGoogle Scholar
  26. 26.
    Buerk DG, Atochin DN, Riva CE (2003) Investigating the role of nitric oxide in regulating blood flow and oxygen delivery from in vivo electrochemical measurements in eye and brain. Adv Exp Med Biol 530:359–370PubMedGoogle Scholar
  27. 27.
    Faraci FM, Brian JE Jr (1995) 7-Nitroindazole inhibits brain nitric oxide synthase and cerebral vasodilatation in response to N-methyl-d-aspartate. Stroke 26:2172–2175; discussion 2176Google Scholar
  28. 28.
    Zhang F, Xu S, Iadecola C (1995) Role of nitric oxide and acetylcholine in neocortical hyperemia elicited by basal forebrain stimulation: evidence for an involvement of endothelial nitric oxide. Neuroscience 69:1195–1204PubMedGoogle Scholar
  29. 29.
    Wu DM, Kawamura H, Sakagami K, Kobayashi M, Puro DG (2003) Cholinergic regulation of pericyte-containing retinal microvessels. Am J Physiol Heart Circ Physiol 284:H2083–H2090PubMedGoogle Scholar
  30. 30.
    Filosa JA, Bonev AD, Straub SV, Meredith AL, Wilkerson MK, Aldrich RW, Nelson MT (2006) Local potassium signaling couples neuronal activity to vasodilation in the brain. Nat Neurosci 9:1397–1403PubMedGoogle Scholar
  31. 31.
    Sokoya EM, Burns AR, Setiawan CT, Coleman HA, Parkington HC, Tare M (2006) Evidence for the involvement of myoendothelial gap junctions in EDHF-mediated relaxation in the rat middle cerebral artery. Am J Physiol Heart Circ Physiol 291: H385–H393PubMedGoogle Scholar
  32. 32.
    Cox SB, Woolsey TA, Rovainen CM (1993) Localized dynamic changes in cortical blood flow with whisker stimulation corresponds to matched vascular and neuronal architecture of rat barrels. J Cereb Blood Flow Metab 13:899–913PubMedGoogle Scholar
  33. 33.
    Erinjeri JP, Woolsey TA (2002) Spatial integration of vascular changes with neural activity in mouse cortex. J Cereb Blood Flow Metab 22:353–360PubMedGoogle Scholar
  34. 34.
    Ngai AC, Ko KR, Morii S, Winn HR (1988) Effect of sciatic nerve stimulation on pial arterioles in rats. Am J Physiol 254:H133–H139PubMedGoogle Scholar
  35. 35.
    Busse R, Fleming I (2003) Regulation of endothelium-derived vasoactive autacoid production by hemodynamic forces. Trends Pharmacol Sci 24:24–29PubMedGoogle Scholar
  36. 36.
    Peppiatt CM, Howarth C, Mobbs P, Attwell D (2006) Bidirectional control of CNS capillary diameter by pericytes. Nature 443:700–704PubMedGoogle Scholar
  37. 37.
    Pelligrino DA (2006) Regulation of the cerebral circulation. J Appl Physiol 100:3–4PubMedGoogle Scholar
  38. 38.
    Mintun MA, Lundstrom BN, Snyder AZ, Vlassenko AG, Shulman GL, Raichle ME (2001) Blood flow and oxygen delivery to human brain during functional activity: theoretical modeling and experimental data. Proc Natl Acad Sci USA 98:6859–6864PubMedGoogle Scholar
  39. 39.
    Powers WJ, Hirsch IB, Cryer PE (1996) Effect of stepped hypoglycemia on regional cerebral blood flow response to physiological brain activation. Am J Physiol 270:H554–H559PubMedGoogle Scholar
  40. 40.
    Gotoh J, Kuang TY, Nakao Y, Cohen DM, Melzer P, Itoh Y, Pak H, Pettigrew K, Sokoloff L (2001) Regional differences in mechanisms of cerebral circulatory response to neuronal activation. Am J Physiol Heart Circ Physiol 280:H821–H829PubMedGoogle Scholar
  41. 41.
    Koehler RC, Gebremedhin D, Harder DR (2006) Role of astrocytes in cerebrovascular regulation. J Appl Physiol 100:307–317PubMedGoogle Scholar
  42. 42.
    White RP, Hindley C, Bloomfield PM, Cunningham VJ, Vallance P, Brooks DJ, Markus HS (1999) The effect of the nitric oxide synthase inhibitor L-NMMA on basal CBF and vasoneuronal coupling in man: a PET study. J Cereb Blood Flow Metab 19:673–678PubMedGoogle Scholar
  43. 43.
    Newman EA (2003) New roles for astrocytes: regulation of synaptic transmission. Trends Neurosci 26:536–542PubMedGoogle Scholar
  44. 44.
    Ngai AC, Coyne EF, Meno JR, West GA, Winn HR (2001) Receptor subtypes mediating adenosine-induced dilation of cerebral arterioles. Am J Physiol Heart Circ Physiol 280:H2329–H2335PubMedGoogle Scholar
  45. 45.
    Shin HK, Shin YW, Hong KW (2000) Role of adenosine A(2B) receptors in vasodilation of rat pial artery and cerebral blood flow autoregulation. Am J Physiol Heart Circ Physiol 278: H339–H344PubMedGoogle Scholar
  46. 46.
    Saez JC, Retamal MA, Basilio D, Bukauskas FF, Bennett MV (2005) Connexin-based gap junction hemichannels: gating mechanisms. Biochim Biophys Acta 1711:215–224PubMedGoogle Scholar
  47. 47.
    Stout CE, Costantin JL, Naus CC, Charles AC (2002) Intercellular calcium signaling in astrocytes via ATP release through connexin hemichannels. J Biol Chem 277:10482–10488PubMedGoogle Scholar
  48. 48.
    Alloisio S, Cugnoli C, Ferroni S, Nobile M (2004) Differential modulation of ATP-induced calcium signalling by A1 and A2 adenosine receptors in cultured cortical astrocytes. Br J Pharmacol 141:935–942PubMedGoogle Scholar
  49. 49.
    Jimenez AI, Castro E, Mirabet M, Franco R, Delicado EG, Miras-Portugal MT (1999) Potentiation of ATP calcium responses by A2B receptor stimulation and other signals coupled to Gs proteins in type-1 cerebellar astrocytes. Glia. 26:119–128PubMedGoogle Scholar
  50. 50.
    Peakman MC, Hill SJ (1994) Adenosine A2B-receptor-mediated cyclic AMP accumulation in primary rat astrocytes. Br J Pharmacol 111:191–198PubMedGoogle Scholar
  51. 51.
    Allaman I, Lengacher S, Magistretti PJ, Pellerin L (2003) A2B receptor activation promotes glycogen synthesis in astrocytes through modulation of gene expression. Am J Physiol Cell Physiol 284:C696–C704PubMedGoogle Scholar
  52. 52.
    Pilitsis JG, Kimelberg HK (1998) Adenosine receptor mediated stimulation of intracellular calcium in acutely isolated astrocytes. Brain Res 798:294–303PubMedGoogle Scholar
  53. 53.
    Krimer LS, Muly EC 3rd, Williams GV, Goldman-Rakic PS (1998) Dopaminergic regulation of cerebral cortical microcirculation. Nat Neurosci 1:286–289PubMedGoogle Scholar
  54. 54.
    Niwa K, Araki E, Morham SG, Ross ME, Iadecola C (2000) Cyclooxygenase-2 contributes to functional hyperemia in whisker-barrel cortex. J Neurosci 20:763–770PubMedGoogle Scholar
  55. 55.
    Niwa K, Haensel C, Ross ME, Iadecola C (2001) Cyclooxygenase-1 participates in selected vasodilator responses of the cerebral circulation. Circ Res 88:600–608PubMedGoogle Scholar
  56. 56.
    Verbeek MM, de Waal RM, Schipper JJ, Van Nostrand WE (1997) Rapid degeneration of cultured human brain pericytes by amyloid beta protein. J Neurochem 68:1135–1141PubMedCrossRefGoogle Scholar
  57. 57.
    Hirase T, Staddon JM, Saitou M, Ando-Akatsuka Y, Itoh M, Furuse M, Fujimoto K, Tsukita S, Rubin LL (1997) Occludin as a possible determinant of tight junction permeability in endothelial cells. J Cell Sci 110 (Pt 14):1603–1613PubMedGoogle Scholar
  58. 58.
    Estrada C, Bready JV, Berliner JA, Pardridge WM, Cancilla PA (1990) Astrocyte growth stimulation by a soluble factor produced by cerebral endothelial cells in vitro. J Neuropathol Exp Neurol 49:539–549PubMedGoogle Scholar
  59. 59.
    Mi H, Haeberle H, Barres BA (2001) Induction of astrocyte differentiation by endothelial cells. J Neurosci 21:1538–1547PubMedGoogle Scholar
  60. 60.
    Mizuguchi H, Utoguchi N, Mayumi T (1997) Preparation of glial extracellular matrix: a novel method to analyze glial-endothelial cell interaction. Brain Res Brain Res Protoc 1:339–343PubMedGoogle Scholar
  61. 61.
    Schroeter ML, Mertsch K, Giese H, Muller S, Sporbert A, Hickel B, Blasig IE (1999) Astrocytes enhance radical defence in capillary endothelial cells constituting the blood–brain barrier. FEBS Lett 449:241–244PubMedGoogle Scholar
  62. 62.
    Regina A, Morchoisne S, Borson ND, McCall AL, Drewes LR, Roux F (2001) Factor(s) released by glucose-deprived astrocytes enhance glucose transporter expression and activity in rat brain endothelial cells. Biochim Biophys Acta 1540:233–242PubMedGoogle Scholar
  63. 63.
    Braet K, Cabooter L, Paemeleire K, Leybaert L (2004) Calcium signal communication in the central nervous system. Biol Cell 96:79–91PubMedGoogle Scholar
  64. 64.
    Leybaert L, Cabooter L, Braet K (2004) Calcium signal communication between glial and vascular brain cells. Acta Neurol Belg 104:51–56PubMedGoogle Scholar
  65. 65.
    Bezzi P, Domercq M, Brambilla L, Galli R, Schols D, De Clercq E, Vescovi A, Bagetta G, Kollias G, Meldolesi J, Volterra A (2001) CXCR4-activated astrocyte glutamate release via TNFalpha: amplification by microglia triggers neurotoxicity. Nat Neurosci 4:702–710PubMedGoogle Scholar
  66. 66.
    Hansson E, Ronnback L (2003) Glial neuronal signaling in the central nervous system. Faseb J 17:341–348PubMedGoogle Scholar
  67. 67.
    Huber JD, Egleton RD, Davis TP (2001) Molecular physiology and pathophysiology of tight junctions in the blood–brain barrier. Trends Neurosci 24:719–725PubMedGoogle Scholar
  68. 68.
    Pardrige WM (2003) Molecular biology of the blood brain barrier. In: The blood brain barrier. Humana Press, Totowa, NJ, pp 385–397Google Scholar
  69. 69.
    Lee G, Bendayan R (2004) Functional expression and localization of P-glycoprotein in the central nervous system: relevance to the pathogenesis and treatment of neurological disorders. Pharm Res 21:1313–1330PubMedGoogle Scholar
  70. 70.
    Berzin TM, Zipser BD, Rafii MS, Kuo-Leblanc V, Yancopoulos GD, Glass DJ, Fallon JR, Stopa EG (2000) Agrin and microvascular damage in Alzheimer’s disease. Neurobiol Aging 21:349–355PubMedGoogle Scholar
  71. 71.
    Kalaria RN (1999) The blood–brain barrier and cerebrovascular pathology in Alzheimer’s disease. Ann N Y Acad Sci 893:113–125PubMedGoogle Scholar
  72. 72.
    Kortekaas R, Leenders KL, van Oostrom JC, Vaalburg W, Bart J, Willemsen AT, Hendrikse NH (2005) Blood–brain barrier dysfunction in parkinsonian midbrain in vivo. Ann Neurol 57:176–179PubMedGoogle Scholar
  73. 73.
    Minagar A, Alexander JS (2003) Blood–brain barrier disruption in multiple sclerosis. Mult Scler 9:540–549PubMedGoogle Scholar
  74. 74.
    Wolburg H, Wolburg-Buchholz K, Kraus J, Rascher-Eggstein G, Liebner S, Hamm S, Duffner F, Grote EH, Risau W, Engelhardt B (2003) Localization of claudin-3 in tight junctions of the blood–brain barrier is selectively lost during experimental autoimmune encephalomyelitis and human glioblastoma multiforme. Acta Neuropathol (Berl) 105:586–592Google Scholar
  75. 75.
    Abbott NJ (2002) Astrocyte-endothelial interactions and blood–brain barrier permeability. J Anat 200:629–638PubMedGoogle Scholar
  76. 76.
    Marroni M, Marchi N, Cucullo L, Abbott NJ, Signorelli K, Janigro D (2003) Vascular and parenchymal mechanisms in multiple drug resistance: a lesson from human epilepsy. Curr Drug Targets 4:297–304PubMedGoogle Scholar
  77. 77.
    Davies DC (2002) Blood–brain barrier breakdown in septic encephalopathy and brain tumours. J Anat 200:639–646PubMedGoogle Scholar
  78. 78.
    Liebner S, Fischmann A, Rascher G, Duffner F, Grote EH, Kalbacher H, Wolburg H (2000) Claudin-1 and claudin-5 expression and tight junction morphology are altered in blood vessels of human glioblastoma multiforme. Acta Neuropathol (Berl) 100:323–331Google Scholar
  79. 79.
    Warth A, Kroger S, Wolburg H (2004) Redistribution of aquaporin-4 in human glioblastoma correlates with loss of agrin immunoreactivity from brain capillary basal laminae. Acta Neuropathol (Berl) 107:311–318Google Scholar
  80. 80.
    Carmeliet P (2003) Blood vessels and nerves: common signals, pathways and diseases. Nat Rev Genet 4:710–720PubMedGoogle Scholar
  81. 81.
    Palmer TD, Willhoite AR, Gage FH (2000) Vascular niche for adult hippocampal neurogenesis. J Comp Neurol 425:479–494PubMedGoogle Scholar
  82. 82.
    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 99:11946–11950PubMedGoogle Scholar
  83. 83.
    Jin KL, Mao XO, Greenberg DA (2000) Vascular endothelial growth factor: direct neuroprotective effect in in vitro ischemia. Proc Natl Acad Sci USA 97:10242–10247PubMedGoogle Scholar
  84. 84.
    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 15:1218–1220PubMedGoogle Scholar
  85. 85.
    Ogunshola OO, Antic A, Donoghue MJ, Fan SY, 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 277:11410–11415PubMedGoogle Scholar
  86. 86.
    Silverman WF, Krum JM, Mani N, Rosenstein JM (1999) Vascular, glial and neuronal effects of vascular endothelial growth factor in mesencephalic explant cultures. Neuroscience 90:1529–1541PubMedGoogle Scholar
  87. 87.
    Bagnard D, Vaillant C, Khuth ST, Dufay N, Lohrum M, Puschel AW, Belin MF, Bolz J, Thomasset N (2001) Semaphorin 3A-vascular endothelial growth factor-165 balance mediates migration and apoptosis of neural progenitor cells by the recruitment of shared receptor. J Neurosci 21:3332–3341PubMedGoogle Scholar
  88. 88.
    Miao HQ, Soker S, Feiner L, Alonso JL, Raper JA, Klagsbrun M (1999) Neuropilin-1 mediates collapsin-1/semaphorin III inhibition of endothelial cell motility: functional competition of collapsin-1 and vascular endothelial growth factor-165. J Cell Biol 146:233–242PubMedGoogle Scholar
  89. 89.
    Ciccolini F, Svendsen CN (1998) Fibroblast growth factor 2 (FGF-2) promotes acquisition of epidermal growth factor (EGF) responsiveness in mouse striatal precursor cells: identification of neural precursors responding to both EGF and FGF-2. J Neurosci 18:7869–7880PubMedGoogle Scholar
  90. 90.
    Gage FH, Coates PW, Palmer TD, Kuhn HG, Fisher LJ, Suhonen JO, Peterson DA, Suhr ST, Ray J (1995) Survival and differentiation of adult neuronal progenitor cells transplanted to the adult brain. Proc Natl Acad Sci USA 92:11879–11883PubMedGoogle Scholar
  91. 91.
    Gritti A, Parati EA, Cova L, Frolichsthal P, Galli R, Wanke E, Faravelli L, Morassutti DJ, Roisen F, Nickel DD, Vescovi AL (1996) Multipotential stem cells from the adult mouse brain proliferate and self-renew in response to basic fibroblast growth factor. J Neurosci 16:1091–1100PubMedGoogle Scholar
  92. 92.
    Kilpatrick TJ, Bartlett PF (1995) Cloned multipotential precursors from the mouse cerebrum require FGF-2, whereas glial restricted precursors are stimulated with either FGF-2 or EGF. J Neurosci 15:3653–3661PubMedGoogle Scholar
  93. 93.
    Palmer TD, Takahashi J, Gage FH (1997) The adult rat hippocampus contains primordial neural stem cells. Mol Cell Neurosci 8:389–404PubMedGoogle Scholar
  94. 94.
    Tao Y, Black IB, DiCicco-Bloom E (1996) Neurogenesis in neonatal rat brain is regulated by peripheral injection of basic fibroblast growth factor (bFGF). J Comp Neurol 376:653–663PubMedGoogle Scholar
  95. 95.
    Wagner JP, Black IB, DiCicco-Bloom E (1999) Stimulation of neonatal and adult brain neurogenesis by subcutaneous injection of basic fibroblast growth factor. J Neurosci 19:6006–6016PubMedGoogle Scholar
  96. 96.
    Barres BA, Schmid R, Sendnter M, Raff MC (1993) Multiple extracellular signals are required for long-term oligodendrocyte survival. Development 118:283–295PubMedGoogle Scholar
  97. 97.
    Cameron HA, Hazel TG, McKay RD (1998) Regulation of neurogenesis by growth factors and neurotransmitters. J Neurobiol 36:287–306PubMedGoogle Scholar
  98. 98.
    Wolswijk G, Riddle PN, Noble M (1991) Platelet-derived growth factor is mitogenic for O-2Aadult progenitor cells. Glia 4:495–503PubMedGoogle Scholar
  99. 99.
    Ward NL, Lamanna JC (2004) The neurovascular unit and its growth factors: coordinated response in the vascular and nervous systems. Neurol Res 26:870–883PubMedGoogle Scholar
  100. 100.
    Coulthard MG, Duffy S, Down M, Evans B, Power M, Smith F, Stylianou C, Kleikamp S, Oates A, Lackmann M, Burns GF, Boyd AW (2002) The role of the Eph-ephrin signalling system in the regulation of developmental patterning. Int J Dev Biol 46:375–384PubMedGoogle Scholar
  101. 101.
    Knoll B, Drescher U (2002) Ephrin-As as receptors in topographic projections. Trends Neurosci 25:145–149PubMedGoogle Scholar
  102. 102.
    Gerety SS, Wang HU, Chen ZF, Anderson DJ (1999) Symmetrical mutant phenotypes of the receptor EphB4 and its specific transmembrane ligand ephrin-B2 in cardiovascular development. Mol Cell 4:403–414PubMedGoogle Scholar
  103. 103.
    Wang HU, Chen ZF, Anderson DJ (1998) Molecular distinction and angiogenic interaction between embryonic arteries and veins revealed by ephrin-B2 and its receptor Eph-B4. Cell 93:741–753PubMedGoogle Scholar
  104. 104.
    Wilson BD, Ii M, Park KW, Suli A, Sorensen LK, Larrieu-Lahargue F, Urness LD, Suh W, Asai J, Kock GA, Thorne T, Silver M, Thomas KR, Chien CB, Losordo DW, Li DY (2006) Netrins promote developmental and therapeutic angiogenesis. Science 313:640–644PubMedGoogle Scholar
  105. 105.
    Gassmann M, Lemke G (1997) Neuregulins and neuregulin receptors in neural development. Curr Opin Neurobiol 7:87–92PubMedGoogle Scholar
  106. 106.
    Russell KS, Stern DF, Polverini PJ, Bender JR (1999) Neuregulin activation of ErbB receptors in vascular endothelium leads to angiogenesis. Am J Physiol 277:H2205–H2211PubMedGoogle Scholar
  107. 107.
    Seghezzi G, Patel S, Ren CJ, Gualandris A, Pintucci G, Robbins ES, Shapiro RL, Galloway AC, Rifkin DB, Mignatti P (1998) Fibroblast growth factor-2 (FGF-2) induces vascular endothelial growth factor (VEGF) expression in the endothelial cells of forming capillaries: an autocrine mechanism contributing to angiogenesis. J Cell Biol 141:1659–1673PubMedGoogle Scholar
  108. 108.
    Pepper MS, Mandriota SJ (1998) Regulation of vascular endothelial growth factor receptor-2 (Flk-1) expression in vascular endothelial cells. Exp Cell Res 241:414–425PubMedGoogle Scholar
  109. 109.
    Cobbs CS, Chen J, Greenberg DA, Graham SH (1998) Vascular endothelial growth factor expression in transient focal cerebral ischemia in the rat. Neurosci Lett 249:79–82PubMedGoogle Scholar
  110. 110.
    Krum JM, Rosenstein JM (1998) 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 154:57–65PubMedGoogle Scholar
  111. 111.
    Kuwaki T, Kurihara H, Cao WH, Kurihara Y, Unekawa M, Yazaki Y, Kumada M (1997) Physiological role of brain endothelin in the central autonomic control: from neuron to knockout mouse. Prog Neurobiol 51:545–579PubMedGoogle Scholar
  112. 112.
    Bjornson CR, Rietze RL, Reynolds BA, Magli MC, Vescovi AL (1999) Turning brain into blood: a hematopoietic fate adopted by adult neural stem cells in vivo. Science 283:534–537PubMedGoogle Scholar
  113. 113.
    Liu J, Solway K, Messing RO, Sharp FR (1998) Increased neurogenesis in the dentate gyrus after transient global ischemia in gerbils. J Neurosci 18:7768–7778PubMedGoogle Scholar
  114. 114.
    Arvidsson A, Collin T, Kirik D, Kokaia Z, Lindvall O (2002) Neuronal replacement from endogenous precursors in the adult brain after stroke. Nat Med 8:963–970PubMedGoogle Scholar
  115. 115.
    Parent JM, Vexler ZS, Gong C, Derugin N, Ferriero DM (2002) Rat forebrain neurogenesis and striatal neuron replacement after focal stroke. Ann Neurol 52:802–813PubMedGoogle Scholar
  116. 116.
    Lee SR, Kim HY, Rogowska J, Zhao BQ, Bhide P, Parent JM, Lo EH (2006) Involvement of matrix metalloproteinase in neuroblast cell migration from the subventricular zone after stroke. J Neurosci 26:3491–3495PubMedGoogle Scholar
  117. 117.
    Zhao BQ, Wang S, Kim HY, Storrie H, Rosen BR, Mooney DJ, Wang X, Lo EH (2006) Role of matrix metalloproteinases in delayed cortical responses after stroke. Nat Med 12:441–445PubMedGoogle Scholar
  118. 118.
    Wang L, Zhang Z, Zhang R, Hafner MS, Wong HK, Jiao Z, Chopp M (2004) Erythropoietin up-regulates SOCS2 in neuronal progenitor cells derived from SVZ of adult rat. Neuroreport 15:1225–1229PubMedGoogle Scholar
  119. 119.
    Shyu WC, Lin SZ, Yang HI, Tzeng YS, Pang CY, Yen PS, Li H (2004) Functional recovery of stroke rats induced by granulocyte colony-stimulating factor-stimulated stem cells. Circulation 110:1847–1854PubMedGoogle Scholar
  120. 120.
    Chen J, Zacharek A, Zhang C, Jiang H, Li Y, Roberts C, Lu M, Kapke A, Chopp M (2005) Endothelial nitric oxide synthase regulates brain-derived neurotrophic factor expression and neurogenesis after stroke in mice. J Neurosci 25:2366–2375PubMedGoogle Scholar
  121. 121.
    Weston GC, Haviv I, Rogers PA (2002) Microarray analysis of VEGF-responsive genes in myometrial endothelial cells. Mol Hum Reprod 8:855–863PubMedGoogle Scholar
  122. 122.
    Leventhal C, Rafii S, Rafii D, Shahar A, Goldman SA (1999) Endothelial trophic support of neuronal production and recruitment from the adult mammalian subependyma. Mol Cell Neurosci 13:450–464PubMedGoogle Scholar
  123. 123.
    Shen Q, Goderie SK, Jin L, Karanth N, Sun Y, Abramova N, Vincent P, Pumiglia K, Temple S (2004) Endothelial cells stimulate self-renewal and expand neurogenesis of neural stem cells. Science 304:1338–1340PubMedGoogle Scholar
  124. 124.
    Stankovic K, Rio C, Xia A, Sugawara M, Adams JC, Liberman MC, Corfas G (2004) Survival of adult spiral ganglion neurons requires erbB receptor signaling in the inner ear. J Neurosci 24:8651–8661PubMedGoogle Scholar
  125. 125.
    Esper RM, Loeb JA (2004) Rapid axoglial signaling mediated by neuregulin and neurotrophic factors. J Neurosci 24:6218–6227PubMedGoogle Scholar
  126. 126.
    Fekete DM, Wu DK (2002) Revisiting cell fate specification in the inner ear. Curr Opin Neurobiol 12:35–42PubMedGoogle Scholar
  127. 127.
    Nakamura K, Martin KC, Jackson JK, Beppu K, Woo CW, Thiele CJ (2006) Brain-derived neurotrophic factor activation of TrkB induces vascular endothelial growth factor expression via hypoxia-inducible factor-1alpha in neuroblastoma cells. Cancer Res 66:4249–4255PubMedGoogle Scholar
  128. 128.
    Coull JA, Beggs S, Boudreau D, Boivin D, Tsuda M, Inoue K, Gravel C, Salter MW, De Koninck Y (2005) BDNF from microglia causes the shift in neuronal anion gradient underlying neuropathic pain. Nature 438:1017–1021PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2007

Authors and Affiliations

  • Josephine Lok
    • 1
    • 2
    • 3
  • Punkaj Gupta
    • 3
  • Shuzhen Guo
    • 1
    • 2
  • Woo Jean Kim
    • 1
    • 2
  • Michael J. Whalen
    • 3
  • Klaus van Leyen
    • 1
    • 2
  • Eng H. Lo
    • 1
    • 2
  1. 1.Neuroprotection Research Laboratory, Departments of Radiology and NeurologyMassachusetts General HospitalCharlestownUSA
  2. 2.Program in NeuroscienceHarvard Medical SchoolBostonUSA
  3. 3.Division of Pediatric Critical Care MedicineMassachusetts General HospitalBostonUSA

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