Cellular and Molecular Life Sciences

, Volume 71, Issue 18, pp 3489–3506 | Cite as

Developmental and pathological angiogenesis in the central nervous system

  • Mario Vallon
  • Junlei Chang
  • Haijing Zhang
  • Calvin J. KuoEmail author


Angiogenesis, the formation of new blood vessels from pre-existing vessels, in the central nervous system (CNS) is seen both as a normal physiological response as well as a pathological step in disease progression. Formation of the blood–brain barrier (BBB) is an essential step in physiological CNS angiogenesis. The BBB is regulated by a neurovascular unit (NVU) consisting of endothelial and perivascular cells as well as vascular astrocytes. The NVU plays a critical role in preventing entry of neurotoxic substances and regulation of blood flow in the CNS. In recent years, research on numerous acquired and hereditary disorders of the CNS has increasingly emphasized the role of angiogenesis in disease pathophysiology. Here, we discuss molecular mechanisms of CNS angiogenesis during embryogenesis as well as various pathological states including brain tumor formation, ischemic stroke, arteriovenous malformations, and neurodegenerative diseases.


Central nervous system Angiogenesis Brain tumors Embryogenesis Ischemic stroke 



We thank Dr. Jiyong Zhang of Brown University for his advice and help in preparing the figures. H. Z. was supported by a HHMI Medical Student Research Fellowship. This review was supported by funding from the NIH (1R01NS064517) and American Heart Association (12PILT12850014) to C. J. K.


  1. 1.
    Shepro D, Morel NM (1993) Pericyte physiology. FASEB J 7:1031–1038PubMedGoogle Scholar
  2. 2.
    Armulik A, Genove G, Mae M, Nisancioglu MH, Wallgard E, Niaudet C, He L, Norlin J, Lindblom P, Strittmatter K, Johansson BR, Betsholtz C (2010) Pericytes regulate the blood–brain barrier. Nature 468:557–561. doi: 10.1038/nature09522 PubMedGoogle Scholar
  3. 3.
    Daneman R, Zhou L, Kebede AA, Barres BA (2010) Pericytes are required for blood–brain barrier integrity during embryogenesis. Nature 468:562–566. doi: 10.1038/nature09513 PubMedPubMedCentralGoogle Scholar
  4. 4.
    Abbott NJ, Ronnback L, Hansson E (2006) Astrocyte-endothelial interactions at the blood–brain barrier. Nat Rev Neurosci 7:41–53. doi: 10.1038/nrn1824 PubMedGoogle Scholar
  5. 5.
    Figley CR, Stroman PW (2011) The role(s) of astrocytes and astrocyte activity in neurometabolism, neurovascular coupling, and the production of functional neuroimaging signals. Eur J Neurosci 33:577–588. doi: 10.1111/j.1460-9568.2010.07584.x PubMedGoogle Scholar
  6. 6.
    Figley CR (2011) Lactate transport and metabolism in the human brain: implications for the astrocyte-neuron lactate shuttle hypothesis. J Neurosci 31:4768–4770. doi: 10.1523/JNEUROSCI.6612-10.2011 PubMedGoogle Scholar
  7. 7.
    Zonta M, Angulo MC, Gobbo S, Rosengarten B, Hossmann KA, Pozzan T, Carmignoto G (2003) Neuron-to-astrocyte signaling is central to the dynamic control of brain microcirculation. Nat Neurosci 6:43–50. doi: 10.1038/nn980 PubMedGoogle Scholar
  8. 8.
    Flamme I, Frolich T, Risau W (1997) Molecular mechanisms of vasculogenesis and embryonic angiogenesis. J Cell Physiol 173:206–210. doi: 10.1002/(SICI)1097-4652(199711)173:2<206:AID-JCP22>3.0.CO;2-C PubMedGoogle Scholar
  9. 9.
    Folkman J (1971) Tumor angiogenesis: therapeutic implications. N Engl J Med 285:1182–1186. doi: 10.1056/NEJM197111182852108 PubMedGoogle Scholar
  10. 10.
    Folkman J (1972) Anti-angiogenesis: new concept for therapy of solid tumors. Ann Surg 175:409–416PubMedPubMedCentralGoogle Scholar
  11. 11.
    Fukumura D, Xavier R, Sugiura T, Chen Y, Park EC, Lu N, Selig M, Nielsen G, Taksir T, Jain RK, Seed B (1998) Tumor induction of VEGF promoter activity in stromal cells. Cell 94:715–725PubMedGoogle Scholar
  12. 12.
    Fang J, Shing Y, Wiederschain D, Yan L, Butterfield C, Jackson G, Harper J, Tamvakopoulos G, Moses MA (2000) Matrix metalloproteinase-2 is required for the switch to the angiogenic phenotype in a tumor model. Proc Natl Acad Sci USA 97:3884–3889PubMedPubMedCentralGoogle Scholar
  13. 13.
    Folkman J (2006) Antiangiogenesis in cancer therapy—endostatin and its mechanisms of action. Exp Cell Res 312:594–607. doi: 10.1016/j.yexcr.2005.11.015 PubMedGoogle Scholar
  14. 14.
    Carmeliet P, Jain RK (2000) Angiogenesis in cancer and other diseases. Nature 407:249–257. doi: 10.1038/35025220 PubMedGoogle Scholar
  15. 15.
    O’Reilly MS, Holmgren L, Shing Y, Chen C, Rosenthal RA, Moses M, Lane WS, Cao Y, Sage EH, Folkman J (1994) Angiostatin: a novel angiogenesis inhibitor that mediates the suppression of metastases by a Lewis lung carcinoma. Cell 79:315–328PubMedGoogle Scholar
  16. 16.
    Dameron KM, Volpert OV, Tainsky MA, Bouck N (1994) Control of angiogenesis in fibroblasts by p53 regulation of thrombospondin-1. Science 265:1582–1584PubMedGoogle Scholar
  17. 17.
    Good DJ, Polverini PJ, Rastinejad F, Le Beau MM, Lemons RS, Frazier WA, Bouck NP (1990) A tumor suppressor-dependent inhibitor of angiogenesis is immunologically and functionally indistinguishable from a fragment of thrombospondin. Proc Natl Acad Sci USA 87:6624–6628PubMedPubMedCentralGoogle Scholar
  18. 18.
    Aller SG, Yu J, Ward A, Weng Y, Chittaboina S, Zhuo R, Harrell PM, Trinh YT, Zhang Q, Urbatsch IL, Chang G (2009) Structure of P-glycoprotein reveals a molecular basis for poly-specific drug binding. Science 323:1718–1722. doi: 10.1126/science.1168750 PubMedPubMedCentralGoogle Scholar
  19. 19.
    Alavijeh MS, Chishty M, Qaiser MZ, Palmer AM (2005) Drug metabolism and pharmacokinetics, the blood–brain barrier, and central nervous system drug discovery. NeuroRx 2:554–571. doi: 10.1602/neurorx.2.4.554 PubMedPubMedCentralGoogle Scholar
  20. 20.
    Hawkins RA, O’Kane RL, Simpson IA, Vina JR (2006) Structure of the blood–brain barrier and its role in the transport of amino acids. J Nutr 136:218S–226SPubMedGoogle Scholar
  21. 21.
    Schrade A, Sade H, Couraud PO, Romero IA, Weksler BB, Niewoehner J (2012) Expression and localization of claudins-3 and -12 in transformed human brain endothelium. Fluids Barriers CNS 9:6. doi: 10.1186/2045-8118-9-6 PubMedPubMedCentralGoogle Scholar
  22. 22.
    Stewart PA, Wiley MJ (1981) Developing nervous tissue induces formation of blood–brain barrier characteristics in invading endothelial cells: a study using quail–chick transplantation chimeras. Dev Biol 84:183–192PubMedGoogle Scholar
  23. 23.
    Pardridge WM (2005) The blood–brain barrier: bottleneck in brain drug development. NeuroRx 2:3–14. doi: 10.1602/neurorx.2.1.3 PubMedPubMedCentralGoogle Scholar
  24. 24.
    Gabathuler R (2010) Approaches to transport therapeutic drugs across the blood–brain barrier to treat brain diseases. Neurobiol Dis 37:48–57. doi: 10.1016/j.nbd.2009.07.028 PubMedGoogle Scholar
  25. 25.
    Hogan KA, Ambler CA, Chapman DL, Bautch VL (2004) The neural tube patterns vessels developmentally using the VEGF signaling pathway. Development 131:1503–1513. doi: 10.1242/dev.01039 PubMedGoogle Scholar
  26. 26.
    Breier G, Risau W (1996) The role of vascular endothelial growth factor in blood vessel formation. Trends Cell Biol 6:454–456PubMedGoogle Scholar
  27. 27.
    Breier G, Albrecht U, Sterrer S, Risau W (1992) Expression of vascular endothelial growth factor during embryonic angiogenesis and endothelial cell differentiation. Development 114:521–532PubMedGoogle Scholar
  28. 28.
    McCarty JH, Lacy-Hulbert A, Charest A, Bronson RT, Crowley D, Housman D, Savill J, Roes J, Hynes RO (2005) Selective ablation of alphav integrins in the central nervous system leads to cerebral hemorrhage, seizures, axonal degeneration and premature death. Development 132:165–176. doi: 10.1242/dev.01551 PubMedGoogle Scholar
  29. 29.
    Proctor JM, Zang K, Wang D, Wang R, Reichardt LF (2005) Vascular development of the brain requires beta8 integrin expression in the neuroepithelium. J Neurosci 25:9940–9948. doi: 10.1523/JNEUROSCI.3467-05.2005 PubMedPubMedCentralGoogle Scholar
  30. 30.
    Stenman JM, Rajagopal J, Carroll TJ, Ishibashi M, McMahon J, McMahon AP (2008) Canonical Wnt signaling regulates organ-specific assembly and differentiation of CNS vasculature. Science 322:1247–1250. doi: 10.1126/science.1164594 PubMedGoogle Scholar
  31. 31.
    Lyden D, Young AZ, Zagzag D, Yan W, Gerald W, O’Reilly R, Bader BL, Hynes RO, Zhuang Y, Manova K, Benezra R (1999) Id1 and Id3 are required for neurogenesis, angiogenesis and vascularization of tumour xenografts. Nature 401:670–677. doi: 10.1038/44334 PubMedGoogle Scholar
  32. 32.
    Fraidenraich D, Stillwell E, Romero E, Wilkes D, Manova K, Basson CT, Benezra R (2004) Rescue of cardiac defects in id knockout embryos by injection of embryonic stem cells. Science 306:247–252. doi: 10.1126/science.1102612 PubMedPubMedCentralGoogle Scholar
  33. 33.
    Mu Z, Yang Z, Yu D, Zhao Z, Munger JS (2008) TGFbeta1 and TGFbeta3 are partially redundant effectors in brain vascular morphogenesis. Mech Dev 125:508–516. doi: 10.1016/j.mod.2008.01.003 PubMedGoogle Scholar
  34. 34.
    Kuhnert F, Mancuso MR, Shamloo A, Wang HT, Choksi V, Florek M, Su H, Fruttiger M, Young WL, Heilshorn SC, Kuo CJ (2010) Essential regulation of CNS angiogenesis by the orphan G protein-coupled receptor GPR124. Science 330:985–989. doi: 10.1126/science.1196554 PubMedPubMedCentralGoogle Scholar
  35. 35.
    Anderson KD, Pan L, Yang XM, Hughes VC, Walls JR, Dominguez MG, Simmons MV, Burfeind P, Xue Y, Wei Y, Macdonald LE, Thurston G, Daly C, Lin HC, Economides AN, Valenzuela DM, Murphy AJ, Yancopoulos GD, Gale NW (2011) Angiogenic sprouting into neural tissue requires Gpr124, an orphan G protein-coupled receptor. Proc Natl Acad Sci USA 108:2807–2812. doi: 10.1073/pnas.1019761108 PubMedPubMedCentralGoogle Scholar
  36. 36.
    Cullen M, Elzarrad MK, Seaman S, Zudaire E, Stevens J, Yang MY, Li X, Chaudhary A, Xu L, Hilton MB, Logsdon D, Hsiao E, Stein EV, Cuttitta F, Haines DC, Nagashima K, Tessarollo L, St Croix B (2011) GPR124, an orphan G protein-coupled receptor, is required for CNS-specific vascularization and establishment of the blood–brain barrier. Proc Natl Acad Sci USA 108:5759–5764. doi: 10.1073/pnas.1017192108 PubMedPubMedCentralGoogle Scholar
  37. 37.
    Ghosh R, Lipson KL, Sargent KE, Mercurio AM, Hunt JS, Ron D, Urano F (2010) Transcriptional regulation of VEGF-A by the unfolded protein response pathway. PLoS One 5:e9575. doi: 10.1371/journal.pone.0009575 PubMedPubMedCentralGoogle Scholar
  38. 38.
    Wang Y, Alam GN, Ning Y, Visioli F, Dong Z, Nor JE, Polverini PJ (2012) The unfolded protein response induces the angiogenic switch in human tumor cells through the PERK/ATF4 pathway. Cancer Res 72:5396–5406. doi: 10.1158/0008-5472.CAN-12-0474 PubMedPubMedCentralGoogle Scholar
  39. 39.
    Ferrara N, Gerber HP, LeCouter J (2003) The biology of VEGF and its receptors. Nat Med 9:669–676. doi: 10.1038/nm0603-669 PubMedGoogle Scholar
  40. 40.
    Raab S, Beck H, Gaumann A, Yuce A, Gerber HP, Plate K, Hammes HP, Ferrara N, Breier G (2004) Impaired brain angiogenesis and neuronal apoptosis induced by conditional homozygous inactivation of vascular endothelial growth factor. Thromb Haemost 91:595–605. doi: 10.1160/TH03-09-0582 PubMedGoogle Scholar
  41. 41.
    Haigh JJ, Morelli PI, Gerhardt H, Haigh K, Tsien J, Damert A, Miquerol L, Muhlner U, Klein R, Ferrara N, Wagner EF, Betsholtz C, Nagy A (2003) Cortical and retinal defects caused by dosage-dependent reductions in VEGF-A paracrine signaling. Dev Biol 262:225–241PubMedGoogle Scholar
  42. 42.
    Gerhardt H, Golding M, Fruttiger M, Ruhrberg C, Lundkvist A, Abramsson A, Jeltsch M, Mitchell C, Alitalo K, Shima D, Betsholtz C (2003) VEGF guides angiogenic sprouting utilizing endothelial tip cell filopodia. J Cell Biol 161:1163–1177. doi: 10.1083/jcb.200302047 PubMedPubMedCentralGoogle Scholar
  43. 43.
    Olsson AK, Dimberg A, Kreuger J, Claesson-Welsh L (2006) VEGF receptor signalling—in control of vascular function. Nat Rev Mol Cell Biol 7:359–371. doi: 10.1038/nrm1911 PubMedGoogle Scholar
  44. 44.
    Ruhrberg C, Gerhardt H, Golding M, Watson R, Ioannidou S, Fujisawa H, Betsholtz C, Shima DT (2002) Spatially restricted patterning cues provided by heparin-binding VEGF-A control blood vessel branching morphogenesis. Genes Dev 16:2684–2698. doi: 10.1101/gad.242002 PubMedPubMedCentralGoogle Scholar
  45. 45.
    Perk J, Iavarone A, Benezra R (2005) Id family of helix-loop-helix proteins in cancer. Nat Rev Cancer 5:603–614. doi: 10.1038/nrc1673 PubMedGoogle Scholar
  46. 46.
    Yokota Y (2001) Id and development. Oncogene 20:8290–8298. doi: 10.1038/sj.onc.1205090 PubMedGoogle Scholar
  47. 47.
    Zhao Q, Beck AJ, Vitale JM, Schneider JS, Gao S, Chang C, Elson G, Leibovich SJ, Park JY, Tian B, Nam HS, Fraidenraich D (2011) Developmental ablation of Id1 and Id3 genes in the vasculature leads to postnatal cardiac phenotypes. Dev Biol 349:53–64. doi: 10.1016/j.ydbio.2010.10.004 PubMedPubMedCentralGoogle Scholar
  48. 48.
    Liebner S, Corada M, Bangsow T, Babbage J, Taddei A, Czupalla CJ, Reis M, Felici A, Wolburg H, Fruttiger M, Taketo MM, von Melchner H, Plate KH, Gerhardt H, Dejana E (2008) Wnt/beta-catenin signaling controls development of the blood–brain barrier. J Cell Biol 183:409–417. doi: 10.1083/jcb.200806024 PubMedPubMedCentralGoogle Scholar
  49. 49.
    Daneman R, Agalliu D, Zhou L, Kuhnert F, Kuo CJ, Barres BA (2009) Wnt/beta-catenin signaling is required for CNS, but not non-CNS, angiogenesis. Proc Natl Acad Sci USA 106:641–646. doi: 10.1073/pnas.0805165106 PubMedPubMedCentralGoogle Scholar
  50. 50.
    van Amerongen R, Nusse R (2009) Towards an integrated view of Wnt signaling in development. Development 136:3205–3214. doi: 10.1242/dev.033910 PubMedGoogle Scholar
  51. 51.
    Zhu J, Motejlek K, Wang D, Zang K, Schmidt A, Reichardt LF (2002) Beta8 integrins are required for vascular morphogenesis in mouse embryos. Development 129:2891–2903PubMedPubMedCentralGoogle Scholar
  52. 52.
    Bader BL, Rayburn H, Crowley D, Hynes RO (1998) Extensive vasculogenesis, angiogenesis, and organogenesis precede lethality in mice lacking all alpha v integrins. Cell 95:507–519PubMedGoogle Scholar
  53. 53.
    Kulkarni AB, Huh CG, Becker D, Geiser A, Lyght M, Flanders KC, Roberts AB, Sporn MB, Ward JM, Karlsson S (1993) Transforming growth factor beta 1 null mutation in mice causes excessive inflammatory response and early death. Proc Natl Acad Sci USA 90:770–774PubMedPubMedCentralGoogle Scholar
  54. 54.
    Shull MM, Ormsby I, Kier AB, Pawlowski S, Diebold RJ, Yin M, Allen R, Sidman C, Proetzel G, Calvin D et al (1992) Targeted disruption of the mouse transforming growth factor-beta 1 gene results in multifocal inflammatory disease. Nature 359:693–699. doi: 10.1038/359693a0 PubMedPubMedCentralGoogle Scholar
  55. 55.
    Sanford LP, Ormsby I, Gittenberger-de Groot AC, Sariola H, Friedman R, Boivin GP, Cardell EL, Doetschman T (1997) TGFbeta2 knockout mice have multiple developmental defects that are non-overlapping with other TGFbeta knockout phenotypes. Development 124:2659–2670PubMedPubMedCentralGoogle Scholar
  56. 56.
    Kaartinen V, Voncken JW, Shuler C, Warburton D, Bu D, Heisterkamp N, Groffen J (1995) Abnormal lung development and cleft palate in mice lacking TGF-beta 3 indicates defects of epithelial-mesenchymal interaction. Nat Genet 11:415–421. doi: 10.1038/ng1295-415 PubMedGoogle Scholar
  57. 57.
    Proetzel G, Pawlowski SA, Wiles MV, Yin M, Boivin GP, Howles PN, Ding J, Ferguson MW, Doetschman T (1995) Transforming growth factor-beta 3 is required for secondary palate fusion. Nat Genet 11:409–414. doi: 10.1038/ng1295-409 PubMedGoogle Scholar
  58. 58.
    Bohnsack BL, Hirschi KK (2004) Red light, green light: signals that control endothelial cell proliferation during embryonic vascular development. Cell Cycle 3:1506–1511PubMedGoogle Scholar
  59. 59.
    Perrella MA, Jain MK, Lee ME (1998) Role of TGF-beta in vascular development and vascular reactivity. Miner Electrolyte Metab 24:136–143PubMedGoogle Scholar
  60. 60.
    Dickson MC, Martin JS, Cousins FM, Kulkarni AB, Karlsson S, Akhurst RJ (1995) Defective haematopoiesis and vasculogenesis in transforming growth factor-beta 1 knockout mice. Development 121:1845–1854PubMedGoogle Scholar
  61. 61.
    Sridurongrit S, Larsson J, Schwartz R, Ruiz-Lozano P, Kaartinen V (2008) Signaling via the Tgf-beta type I receptor Alk5 in heart development. Dev Biol 322:208–218. doi: 10.1016/j.ydbio.2008.07.038 PubMedPubMedCentralGoogle Scholar
  62. 62.
    Robson A, Allinson KR, Anderson RH, Henderson DJ, Arthur HM (2010) The TGFbeta type II receptor plays a critical role in the endothelial cells during cardiac development. Dev Dyn 239:2435–2442. doi: 10.1002/dvdy.22376 PubMedGoogle Scholar
  63. 63.
    Annes JP, Rifkin DB, Munger JS (2002) The integrin alphaVbeta6 binds and activates latent TGFbeta3. FEBS Lett 511:65–68PubMedGoogle Scholar
  64. 64.
    Araya J, Cambier S, Morris A, Finkbeiner W, Nishimura SL (2006) Integrin-mediated transforming growth factor-beta activation regulates homeostasis of the pulmonary epithelial-mesenchymal trophic unit. Am J Pathol 169:405–415PubMedPubMedCentralGoogle Scholar
  65. 65.
    Mu D, Cambier S, Fjellbirkeland L, Baron JL, Munger JS, Kawakatsu H, Sheppard D, Broaddus VC, Nishimura SL (2002) The integrin alpha(v)beta8 mediates epithelial homeostasis through MT1-MMP-dependent activation of TGF-beta1. J Cell Biol 157:493–507. doi: 10.1083/jcb.200109100 PubMedPubMedCentralGoogle Scholar
  66. 66.
    Munger JS, Huang X, Kawakatsu H, Griffiths MJ, Dalton SL, Wu J, Pittet JF, Kaminski N, Garat C, Matthay MA, Rifkin DB, Sheppard D (1999) The integrin alpha v beta 6 binds and activates latent TGF beta 1: a mechanism for regulating pulmonary inflammation and fibrosis. Cell 96:319–328PubMedGoogle Scholar
  67. 67.
    Annes JP, Munger JS, Rifkin DB (2003) Making sense of latent TGFbeta activation. J Cell Sci 116:217–224PubMedGoogle Scholar
  68. 68.
    Annes JP, Chen Y, Munger JS, Rifkin DB (2004) Integrin alphaVbeta6-mediated activation of latent TGF-beta requires the latent TGF-beta binding protein-1. J Cell Biol 165:723–734. doi: 10.1083/jcb.200312172 PubMedPubMedCentralGoogle Scholar
  69. 69.
    Yang Z, Mu Z, Dabovic B, Jurukovski V, Yu D, Sung J, Xiong X, Munger JS (2007) Absence of integrin-mediated TGFbeta1 activation in vivo recapitulates the phenotype of TGFbeta1-null mice. J Cell Biol 176:787–793. doi: 10.1083/jcb.200611044 PubMedPubMedCentralGoogle Scholar
  70. 70.
    Krieglstein K, Strelau J, Schober A, Sullivan A, Unsicker K (2002) TGF-beta and the regulation of neuron survival and death. J Physiol Paris 96:25–30PubMedGoogle Scholar
  71. 71.
    Pelton RW, Dickinson ME, Moses HL, Hogan BL (1990) In situ hybridization analysis of TGF beta 3 RNA expression during mouse development: comparative studies with TGF beta 1 and beta 2. Development 110:609–620PubMedGoogle Scholar
  72. 72.
    Pelton RW, Saxena B, Jones M, Moses HL, Gold LI (1991) Immunohistochemical localization of TGF beta 1, TGF beta 2, and TGF beta 3 in the mouse embryo: expression patterns suggest multiple roles during embryonic development. J Cell Biol 115:1091–1105PubMedGoogle Scholar
  73. 73.
    Cambier S, Gline S, Mu D, Collins R, Araya J, Dolganov G, Einheber S, Boudreau N, Nishimura SL (2005) Integrin alpha(v)beta8-mediated activation of transforming growth factor-beta by perivascular astrocytes: an angiogenic control switch. Am J Pathol 166:1883–1894PubMedPubMedCentralGoogle Scholar
  74. 74.
    Jemal A, Murray T, Ward E, Samuels A, Tiwari RC, Ghafoor A, Feuer EJ, Thun MJ (2005) Cancer statistics, 2005. CA Cancer J Clin 55:10–30PubMedGoogle Scholar
  75. 75.
    Furnari FB, Fenton T, Bachoo RM, Mukasa A, Stommel JM, Stegh A, Hahn WC, Ligon KL, Louis DN, Brennan C, Chin L, DePinho RA, Cavenee WK (2007) Malignant astrocytic glioma: genetics, biology, and paths to treatment. Genes Dev 21:2683–2710. doi: 10.1101/gad.1596707 PubMedGoogle Scholar
  76. 76.
    Meyer MA (2008) Malignant gliomas in adults. N Engl J Med 359:1850; author reply 1850. doi:  10.1056/NEJMc086380
  77. 77.
    Behin A, Hoang-Xuan K, Carpentier AF, Delattre JY (2003) Primary brain tumours in adults. Lancet 361:323–331. doi: 10.1016/S0140-6736(03)12328-8 PubMedGoogle Scholar
  78. 78.
    Fidler IJ, Yano S, Zhang RD, Fujimaki T, Bucana CD (2002) The seed and soil hypothesis: vascularisation and brain metastases. Lancet Oncol 3:53–57PubMedGoogle Scholar
  79. 79.
    Yuan F, Salehi HA, Boucher Y, Vasthare US, Tuma RF, Jain RK (1994) Vascular permeability and microcirculation of gliomas and mammary carcinomas transplanted in rat and mouse cranial windows. Cancer Res 54:4564–4568PubMedGoogle Scholar
  80. 80.
    Hobbs SK, Monsky WL, Yuan F, Roberts WG, Griffith L, Torchilin VP, Jain RK (1998) Regulation of transport pathways in tumor vessels: role of tumor type and microenvironment. Proc Natl Acad Sci USA 95:4607–4612PubMedPubMedCentralGoogle Scholar
  81. 81.
    Monsky WL, Fukumura D, Gohongi T, Ancukiewcz M, Weich HA, Torchilin VP, Yuan F, Jain RK (1999) Augmentation of transvascular transport of macromolecules and nanoparticles in tumors using vascular endothelial growth factor. Cancer Res 59:4129–4135PubMedGoogle Scholar
  82. 82.
    Fukumura D, Xu L, Chen Y, Gohongi T, Seed B, Jain RK (2001) Hypoxia and acidosis independently up-regulate vascular endothelial growth factor transcription in brain tumors in vivo. Cancer Res 61:6020–6024PubMedGoogle Scholar
  83. 83.
    Izumi Y, Xu L, di Tomaso E, Fukumura D, Jain RK (2002) Tumour biology: herceptin acts as an anti-angiogenic cocktail. Nature 416:279–280. doi: 10.1038/416279b PubMedGoogle Scholar
  84. 84.
    Bullitt E, Zeng D, Gerig G, Aylward S, Joshi S, Smith JK, Lin W, Ewend MG (2005) Vessel tortuosity and brain tumor malignancy: a blinded study. Acad Radiol 12:1232–1240. doi: 10.1016/j.acra.2005.05.027 PubMedPubMedCentralGoogle Scholar
  85. 85.
    Deeken JF, Loscher W (2007) The blood–brain barrier and cancer: transporters, treatment, and Trojan horses. Clin Cancer Res 13:1663–1674. doi: 10.1158/1078-0432.CCR-06-2854 PubMedGoogle Scholar
  86. 86.
    Winkler F, Kozin SV, Tong RT, Chae SS, Booth MF, Garkavtsev I, Xu L, Hicklin DJ, Fukumura D, di Tomaso E, Munn LL, Jain RK (2004) Kinetics of vascular normalization by VEGFR2 blockade governs brain tumor response to radiation: role of oxygenation, angiopoietin-1, and matrix metalloproteinases. Cancer Cell 6:553–563. doi: 10.1016/j.ccr.2004.10.011 PubMedGoogle Scholar
  87. 87.
    Plate KH, Mennel HD (1995) Vascular morphology and angiogenesis in glial tumors. Exp Toxicol Pathol 47:89–94. doi: 10.1016/S0940-2993(11)80292-7 PubMedGoogle Scholar
  88. 88.
    Guo P, Hu B, Gu W, Xu L, Wang D, Huang HJ, Cavenee WK, Cheng SY (2003) Platelet-derived growth factor-B enhances glioma angiogenesis by stimulating vascular endothelial growth factor expression in tumor endothelia and by promoting pericyte recruitment. Am J Pathol 162:1083–1093. doi: 10.1016/S0002-9440(10)63905-3 PubMedPubMedCentralGoogle Scholar
  89. 89.
    Zagzag D, Hooper A, Friedlander DR, Chan W, Holash J, Wiegand SJ, Yancopoulos GD, Grumet M (1999) In situ expression of angiopoietins in astrocytomas identifies angiopoietin-2 as an early marker of tumor angiogenesis. Exp Neurol 159:391–400. doi: 10.1006/exnr.1999.7162 PubMedGoogle Scholar
  90. 90.
    Jain RK (1998) The next frontier of molecular medicine: delivery of therapeutics. Nat Med 4:655–657PubMedGoogle Scholar
  91. 91.
    Monsky WL, Mouta Carreira C, Tsuzuki Y, Gohongi T, Fukumura D, Jain RK (2002) Role of host microenvironment in angiogenesis and microvascular functions in human breast cancer xenografts: mammary fat pad versus cranial tumors. Clin Cancer Res 8:1008–1013PubMedGoogle Scholar
  92. 92.
    Dvorak HF (2002) Vascular permeability factor/vascular endothelial growth factor: a critical cytokine in tumor angiogenesis and a potential target for diagnosis and therapy. J Clin Oncol 20:4368–4380PubMedGoogle Scholar
  93. 93.
    Ferrara N (2004) Vascular endothelial growth factor: basic science and clinical progress. Endocr Rev 25:581–611. doi: 10.1210/er.2003-0027 PubMedGoogle Scholar
  94. 94.
    Fukumura D, Kashiwagi S, Jain RK (2006) The role of nitric oxide in tumour progression. Nat Rev Cancer 6:521–534. doi: 10.1038/nrc1910 PubMedGoogle Scholar
  95. 95.
    Boucher Y, Salehi H, Witwer B, Harsh GRT, Jain RK (1997) Interstitial fluid pressure in intracranial tumours in patients and in rodents. Br J Cancer 75:829–836PubMedPubMedCentralGoogle Scholar
  96. 96.
    Jain RK (1994) Barriers to drug delivery in solid tumors. Sci Am 271:58–65PubMedGoogle Scholar
  97. 97.
    Salmaggi A, Eoli M, Frigerio S, Silvani A, Gelati M, Corsini E, Broggi G, Boiardi A (2003) Intracavitary VEGF, bFGF, IL-8, IL-12 levels in primary and recurrent malignant glioma. J Neurooncol 62:297–303PubMedGoogle Scholar
  98. 98.
    Schmidt NO, Westphal M, Hagel C, Ergun S, Stavrou D, Rosen EM, Lamszus K (1999) Levels of vascular endothelial growth factor, hepatocyte growth factor/scatter factor and basic fibroblast growth factor in human gliomas and their relation to angiogenesis. Int J Cancer 84:10–18PubMedGoogle Scholar
  99. 99.
    Li M, Ransohoff RM (2009) The roles of chemokine CXCL12 in embryonic and brain tumor angiogenesis. Semin Cancer Biol 19:111–115. doi: 10.1016/j.semcancer.2008.11.001 PubMedGoogle Scholar
  100. 100.
    Tso CL, Freije WA, Day A, Chen Z, Merriman B, Perlina A, Lee Y, Dia EQ, Yoshimoto K, Mischel PS, Liau LM, Cloughesy TF, Nelson SF (2006) Distinct transcription profiles of primary and secondary glioblastoma subgroups. Cancer Res 66:159–167. doi: 10.1158/0008-5472.CAN-05-0077 PubMedGoogle Scholar
  101. 101.
    Sun L, Hui AM, Su Q, Vortmeyer A, Kotliarov Y, Pastorino S, Passaniti A, Menon J, Walling J, Bailey R, Rosenblum M, Mikkelsen T, Fine HA (2006) Neuronal and glioma-derived stem cell factor induces angiogenesis within the brain. Cancer Cell 9:287–300. doi: 10.1016/j.ccr.2006.03.003 PubMedGoogle Scholar
  102. 102.
    Reis M, Czupalla CJ, Ziegler N, Devraj K, Zinke J, Seidel S, Heck R, Thom S, Macas J, Bockamp E, Fruttiger M, Taketo MM, Dimmeler S, Plate KH, Liebner S (2012) Endothelial Wnt/beta-catenin signaling inhibits glioma angiogenesis and normalizes tumor blood vessels by inducing PDGF-B expression. J Exp Med 209:1611–1627. doi: 10.1084/jem.20111580 PubMedPubMedCentralGoogle Scholar
  103. 103.
    Vredenburgh JJ, Desjardins A, Herndon JE 2nd, Dowell JM, Reardon DA, Quinn JA, Rich JN, Sathornsumetee S, Gururangan S, Wagner M, Bigner DD, Friedman AH, Friedman HS (2007) Phase II trial of bevacizumab and irinotecan in recurrent malignant glioma. Clin Cancer Res 13:1253–1259. doi: 10.1158/1078-0432.CCR-06-2309 PubMedGoogle Scholar
  104. 104.
    Hellstrom M, Phng LK, Hofmann JJ, Wallgard E, Coultas L, Lindblom P, Alva J, Nilsson AK, Karlsson L, Gaiano N, Yoon K, Rossant J, Iruela-Arispe ML, Kalen M, Gerhardt H, Betsholtz C (2007) Dll4 signalling through Notch1 regulates formation of tip cells during angiogenesis. Nature 445:776–780. doi: 10.1038/nature05571 PubMedGoogle Scholar
  105. 105.
    Phng LK, Gerhardt H (2009) Angiogenesis: a team effort coordinated by notch. Dev Cell 16:196–208. doi: 10.1016/j.devcel.2009.01.015 PubMedGoogle Scholar
  106. 106.
    Noguera-Troise I, Daly C, Papadopoulos NJ, Coetzee S, Boland P, Gale NW, Lin HC, Yancopoulos GD, Thurston G (2006) Blockade of Dll4 inhibits tumour growth by promoting non-productive angiogenesis. Nature 444:1032–1037. doi: 10.1038/nature05355 PubMedGoogle Scholar
  107. 107.
    Yan M, Callahan CA, Beyer JC, Allamneni KP, Zhang G, Ridgway JB, Niessen K, Plowman GD (2010) Chronic DLL4 blockade induces vascular neoplasms. Nature 463:E6–E7. doi: 10.1038/nature08751 PubMedGoogle Scholar
  108. 108.
    Xiong Y, Mahmood A, Chopp M (2010) Angiogenesis, neurogenesis and brain recovery of function following injury. Curr Opin Investig Drugs 11:298–308PubMedPubMedCentralGoogle Scholar
  109. 109.
    Yamashita T, Ninomiya M, Hernandez Acosta P, Garcia-Verdugo JM, Sunabori T, Sakaguchi M, Adachi K, Kojima T, Hirota Y, Kawase T, Araki N, Abe K, Okano H, Sawamoto K (2006) Subventricular zone-derived neuroblasts migrate and differentiate into mature neurons in the post-stroke adult striatum. J Neurosci 26:6627–6636. doi: 10.1523/JNEUROSCI.0149-06.2006 PubMedGoogle Scholar
  110. 110.
    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 13:450–464. doi: 10.1006/mcne.1999.0762 PubMedGoogle Scholar
  111. 111.
    Palmer TD, Willhoite AR, Gage FH (2000) Vascular niche for adult hippocampal neurogenesis. J Comp Neurol 425:479–494PubMedGoogle Scholar
  112. 112.
    Hill WD, Hess DC, Martin-Studdard A, Carothers JJ, Zheng J, Hale D, Maeda M, Fagan SC, Carroll JE, Conway SJ (2004) SDF-1 (CXCL12) is upregulated in the ischemic penumbra following stroke: association with bone marrow cell homing to injury. J Neuropathol Exp Neurol 63:84–96PubMedGoogle Scholar
  113. 113.
    Imitola J, Raddassi K, Park KI, Mueller FJ, Nieto M, Teng YD, Frenkel D, Li J, Sidman RL, Walsh CA, Snyder EY, Khoury SJ (2004) Directed migration of neural stem cells to sites of CNS injury by the stromal cell-derived factor 1alpha/CXC chemokine receptor 4 pathway. Proc Natl Acad Sci USA 101:18117–18122. doi: 10.1073/pnas.0408258102 PubMedPubMedCentralGoogle Scholar
  114. 114.
    Lakhan SE, Kirchgessner A, Hofer M (2009) Inflammatory mechanisms in ischemic stroke: therapeutic approaches. J Transl Med 7:97. doi: 10.1186/1479-5876-7-97 PubMedPubMedCentralGoogle Scholar
  115. 115.
    Obermeier B, Daneman R, Ransohoff RM (2013) Development, maintenance and disruption of the blood–brain barrier. Nat Med 19:1584–1596. doi: 10.1038/nm.3407 PubMedPubMedCentralGoogle Scholar
  116. 116.
    Yilmaz G, Granger DN (2008) Cell adhesion molecules and ischemic stroke. Neurol Res 30:783–793. doi: 10.1179/174313208X341085 PubMedPubMedCentralGoogle Scholar
  117. 117.
    Shichita T, Sugiyama Y, Ooboshi H, Sugimori H, Nakagawa R, Takada I, Iwaki T, Okada Y, Iida M, Cua DJ, Iwakura Y, Yoshimura A (2009) Pivotal role of cerebral interleukin-17-producing gammadeltaT cells in the delayed phase of ischemic brain injury. Nat Med 15:946–950. doi: 10.1038/nm.1999 PubMedGoogle Scholar
  118. 118.
    Liesz A, Suri-Payer E, Veltkamp C, Doerr H, Sommer C, Rivest S, Giese T, Veltkamp R (2009) Regulatory T cells are key cerebroprotective immunomodulators in acute experimental stroke. Nat Med 15:192–199. doi: 10.1038/nm.1927 PubMedGoogle Scholar
  119. 119.
    Lindsberg PJ, Carpen O, Paetau A, Karjalainen-Lindsberg ML, Kaste M (1996) Endothelial ICAM-1 expression associated with inflammatory cell response in human ischemic stroke. Circulation 94:939–945PubMedGoogle Scholar
  120. 120.
    Zhang RL, Chopp M, Li Y, Zaloga C, Jiang N, Jones ML, Miyasaka M, Ward PA (1994) Anti-ICAM-1 antibody reduces ischemic cell damage after transient middle cerebral artery occlusion in the rat. Neurology 44:1747–1751PubMedGoogle Scholar
  121. 121.
    Goussev AV, Zhang Z, Anderson DC, Chopp M (1998) P-selectin antibody reduces hemorrhage and infarct volume resulting from MCA occlusion in the rat. J Neurol Sci 161:16–22PubMedGoogle Scholar
  122. 122.
    Zhang R, Chopp M, Zhang Z, Jiang N, Powers C (1998) The expression of P- and E-selectins in three models of middle cerebral artery occlusion. Brain Res 785:207–214PubMedGoogle Scholar
  123. 123.
    Rallidis LS, Zolindaki MG, Vikelis M, Kaliva K, Papadopoulos C, Kremastinos DT (2009) Elevated soluble intercellular adhesion molecule-1 levels are associated with poor short-term prognosis in middle-aged patients with acute ischaemic stroke. Int J Cardiol 132:216–220. doi: 10.1016/j.ijcard.2007.11.031 PubMedGoogle Scholar
  124. 124.
    Yang Y, Rosenberg GA (2011) Blood–brain barrier breakdown in acute and chronic cerebrovascular disease. Stroke 42:3323–3328. doi: 10.1161/STROKEAHA.110.608257 PubMedPubMedCentralGoogle Scholar
  125. 125.
    Yang Y, Thompson JF, Taheri S, Salayandia VM, McAvoy TA, Hill JW, Yang Y, Estrada EY, Rosenberg GA (2013) Early inhibition of MMP activity in ischemic rat brain promotes expression of tight junction proteins and angiogenesis during recovery. J Cereb Blood Flow Metab 33:1104–1114. doi: 10.1038/jcbfm.2013.56 PubMedPubMedCentralGoogle Scholar
  126. 126.
    Park KP, Rosell A, Foerch C, Xing C, Kim WJ, Lee S, Opdenakker G, Furie KL, Lo EH (2009) Plasma and brain matrix metalloproteinase-9 after acute focal cerebral ischemia in rats. Stroke 40:2836–2842. doi: 10.1161/STROKEAHA.109.554824 PubMedPubMedCentralGoogle Scholar
  127. 127.
    Morancho A, Rosell A, Garcia-Bonilla L, Montaner J (2010) Metalloproteinase and stroke infarct size: role for anti-inflammatory treatment? Ann N Y Acad Sci 1207:123–133. doi: 10.1111/j.1749-6632.2010.05734.x PubMedGoogle Scholar
  128. 128.
    Asahi M, Wang X, Mori T, Sumii T, Jung JC, Moskowitz MA, Fini ME, Lo EH (2001) Effects of matrix metalloproteinase-9 gene knock-out on the proteolysis of blood–brain barrier and white matter components after cerebral ischemia. J Neurosci 21:7724–7732PubMedGoogle Scholar
  129. 129.
    Montaner J, Alvarez-Sabin J, Molina C, Angles A, Abilleira S, Arenillas J, Gonzalez MA, Monasterio J (2001) Matrix metalloproteinase expression after human cardioembolic stroke: temporal profile and relation to neurological impairment. Stroke 32:1759–1766PubMedGoogle Scholar
  130. 130.
    Asahi M, Sumii T, Fini ME, Itohara S, Lo EH (2001) Matrix metalloproteinase 2 gene knockout has no effect on acute brain injury after focal ischemia. NeuroReport 12:3003–3007PubMedGoogle Scholar
  131. 131.
    Candelario-Jalil E, Gonzalez-Falcon A, Garcia-Cabrera M, Leon OS, Fiebich BL (2007) Post-ischaemic treatment with the cyclooxygenase-2 inhibitor nimesulide reduces blood–brain barrier disruption and leukocyte infiltration following transient focal cerebral ischaemia in rats. J Neurochem 100:1108–1120. doi: 10.1111/j.1471-4159.2006.04280.x PubMedGoogle Scholar
  132. 132.
    Beck H, Acker T, Wiessner C, Allegrini PR, Plate KH (2000) Expression of angiopoietin-1, angiopoietin-2, and tie receptors after middle cerebral artery occlusion in the rat. Am J Pathol 157:1473–1483. doi: 10.1016/S0002-9440(10)64786-4 PubMedPubMedCentralGoogle Scholar
  133. 133.
    Marti HJ, Bernaudin M, Bellail A, Schoch H, Euler M, Petit E, Risau W (2000) Hypoxia-induced vascular endothelial growth factor expression precedes neovascularization after cerebral ischemia. Am J Pathol 156:965–976. doi: 10.1016/S0002-9440(10)64964-4 PubMedPubMedCentralGoogle Scholar
  134. 134.
    Hayashi T, Noshita N, Sugawara T, Chan PH (2003) Temporal profile of angiogenesis and expression of related genes in the brain after ischemia. J Cereb Blood Flow Metab 23:166–180PubMedGoogle Scholar
  135. 135.
    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. doi: 10.1097/00004647-200204000-00002 PubMedGoogle Scholar
  136. 136.
    Krupinski J, Kaluza J, Kumar P, Kumar S, Wang JM (1994) Role of angiogenesis in patients with cerebral ischemic stroke. Stroke 25:1794–1798PubMedGoogle Scholar
  137. 137.
    Conway EM, Collen D, Carmeliet P (2001) Molecular mechanisms of blood vessel growth. Cardiovasc Res 49:507–521PubMedGoogle Scholar
  138. 138.
    Fagiani E, Christofori G (2013) Angiopoietins in angiogenesis. Cancer Lett 328:18–26. doi: 10.1016/j.canlet.2012.08.018 PubMedGoogle Scholar
  139. 139.
    Asahara T, Murohara T, Sullivan A, Silver M, van der Zee R, Li T, Witzenbichler B, Schatteman G, Isner JM (1997) Isolation of putative progenitor endothelial cells for angiogenesis. Science 275:964–967PubMedGoogle Scholar
  140. 140.
    Chang J, Li Y, Huang Y, Lam KS, Hoo RL, Wong WT, Cheng KK, Wang Y, Vanhoutte PM, Xu A (2010) Adiponectin prevents diabetic premature senescence of endothelial progenitor cells and promotes endothelial repair by suppressing the p38 MAP kinase/p16INK4A signaling pathway. Diabetes 59:2949–2959. doi: 10.2337/db10-0582 PubMedPubMedCentralGoogle Scholar
  141. 141.
    Chang J, Atochin DN, Li Q, Lam KS, Xu A, Huang PL (2013) Bone marrow-derived circulating endothelial progenitor cells contribute to eNOS-regulated endothelial repair and vasodilation after arterial injury in vivo. J Cardiol Vasc Med 1:1–8Google Scholar
  142. 142.
    Hess DC, Hill WD, Martin-Studdard A, Carroll J, Brailer J, Carothers J (2002) Bone marrow as a source of endothelial cells and NeuN-expressing cells after stroke. Stroke 33:1362–1368PubMedGoogle Scholar
  143. 143.
    Zhang ZG, Zhang L, Jiang Q, Chopp M (2002) Bone marrow-derived endothelial progenitor cells participate in cerebral neovascularization after focal cerebral ischemia in the adult mouse. Circ Res 90:284–288PubMedGoogle Scholar
  144. 144.
    Beck H, Voswinckel R, Wagner S, Ziegelhoeffer T, Heil M, Helisch A, Schaper W, Acker T, Hatzopoulos AK, Plate KH (2003) Participation of bone marrow-derived cells in long-term repair processes after experimental stroke. J Cereb Blood Flow Metab 23:709–717. doi: 10.1097/01.WCB.0000065940.18332.8D PubMedGoogle Scholar
  145. 145.
    Brown WR, Thore CR (2011) Review: cerebral microvascular pathology in ageing and neurodegeneration. Neuropathol Appl Neurobiol 37:56–74. doi: 10.1111/j.1365-2990.2010.01139.x PubMedPubMedCentralGoogle Scholar
  146. 146.
    de la Torre JC, Stefano GB (2000) Evidence that Alzheimer’s disease is a microvascular disorder: the role of constitutive nitric oxide. Brain Res Brain Res Rev 34:119–136PubMedGoogle Scholar
  147. 147.
    Roher AE, Esh C, Kokjohn TA, Kalback W, Luehrs DC, Seward JD, Sue LI, Beach TG (2003) Circle of Willis atherosclerosis is a risk factor for sporadic Alzheimer’s disease. Arterioscler Thromb Vasc Biol 23:2055–2062. doi: 10.1161/01.ATV.0000095973.42032.44 PubMedGoogle Scholar
  148. 148.
    Black JE, Polinsky M, Greenough WT (1989) Progressive failure of cerebral angiogenesis supporting neural plasticity in aging rats. Neurobiol Aging 10:353–358PubMedGoogle Scholar
  149. 149.
    Frenkel-Denkberg G, Gershon D, Levy AP (1999) The function of hypoxia-inducible factor 1 (HIF-1) is impaired in senescent mice. FEBS Lett 462:341–344PubMedGoogle Scholar
  150. 150.
    Rivard A, Fabre JE, Silver M, Chen D, Murohara T, Kearney M, Magner M, Asahara T, Isner JM (1999) Age-dependent impairment of angiogenesis. Circulation 99:111–120PubMedGoogle Scholar
  151. 151.
    Rivard A, Berthou-Soulie L, Principe N, Kearney M, Curry C, Branellec D, Semenza GL, Isner JM (2000) Age-dependent defect in vascular endothelial growth factor expression is associated with reduced hypoxia-inducible factor 1 activity. J Biol Chem 275:29643–29647. doi: 10.1074/jbc.M001029200 PubMedGoogle Scholar
  152. 152.
    Chavez JC, LaManna JC (2003) Hypoxia-inducible factor-1alpha accumulation in the rat brain in response to hypoxia and ischemia is attenuated during aging. Adv Exp Med Biol 510:337–341PubMedGoogle Scholar
  153. 153.
    Rapino C, Bianchi G, Di Giulio C, Centurione L, Cacchio M, Antonucci A, Cataldi A (2005) HIF-1alpha cytoplasmic accumulation is associated with cell death in old rat cerebral cortex exposed to intermittent hypoxia. Aging Cell 4:177–185. doi: 10.1111/j.1474-9726.2005.00161.x PubMedGoogle Scholar
  154. 154.
    Paris D, Patel N, DelleDonne A, Quadros A, Smeed R, Mullan M (2004) Impaired angiogenesis in a transgenic mouse model of cerebral amyloidosis. Neurosci Lett 366:80–85. doi: 10.1016/j.neulet.2004.05.017 PubMedGoogle Scholar
  155. 155.
    Paris D, Townsend K, Quadros A, Humphrey J, Sun J, Brem S, Wotoczek-Obadia M, DelleDonne A, Patel N, Obregon DF, Crescentini R, Abdullah L, Coppola D, Rojiani AM, Crawford F, Sebti SM, Mullan M (2004) Inhibition of angiogenesis by Abeta peptides. Angiogenesis 7:75–85. doi: 10.1023/ PubMedGoogle Scholar
  156. 156.
    Yang SP, Bae DG, Kang HJ, Gwag BJ, Gho YS, Chae CB (2004) Co-accumulation of vascular endothelial growth factor with beta-amyloid in the brain of patients with Alzheimer’s disease. Neurobiol Aging 25:283–290. doi: 10.1016/S0197-4580(03)00111-8 PubMedGoogle Scholar
  157. 157.
    Kalaria RN, Cohen DL, Premkumar DR, Nag S, LaManna JC, Lust WD (1998) Vascular endothelial growth factor in Alzheimer’s disease and experimental cerebral ischemia. Brain Res Mol Brain Res 62:101–105PubMedGoogle Scholar
  158. 158.
    Grammas P, Sanchez A, Tripathy D, Luo E, Martinez J (2011) Vascular signaling abnormalities in Alzheimer disease. Cleve Clin J Med 78(Suppl 1):S50–S53. doi: 10.3949/ccjm.78.s1.09 PubMedGoogle Scholar
  159. 159.
    Schultheiss C, Blechert B, Gaertner FC, Drecoll E, Mueller J, Weber GF, Drzezga A, Essler M (2006) In vivo characterization of endothelial cell activation in a transgenic mouse model of Alzheimer’s disease. Angiogenesis 9:59–65. doi: 10.1007/s10456-006-9030-4 PubMedGoogle Scholar
  160. 160.
    Rosenberg GA (2012) Neurological diseases in relation to the blood–brain barrier. J Cereb Blood Flow Metab 32:1139–1151. doi: 10.1038/jcbfm.2011.197 PubMedPubMedCentralGoogle Scholar
  161. 161.
    Ujiie M, Dickstein DL, Carlow DA, Jefferies WA (2003) Blood–brain barrier permeability precedes senile plaque formation in an Alzheimer disease model. Microcirculation 10:463–470. doi: 10.1038/ PubMedGoogle Scholar
  162. 162.
    Farrall AJ, Wardlaw JM (2009) Blood–brain barrier: ageing and microvascular disease—systematic review and meta-analysis. Neurobiol Aging 30:337–352. doi: 10.1016/j.neurobiolaging.2007.07.015 PubMedGoogle Scholar
  163. 163.
    Deane R, Du Yan S, Submamaryan RK, LaRue B, Jovanovic S, Hogg E, Welch D, Manness L, Lin C, Yu J, Zhu H, Ghiso J, Frangione B, Stern A, Schmidt AM, Armstrong DL, Arnold B, Liliensiek B, Nawroth P, Hofman F, Kindy M, Stern D, Zlokovic B (2003) RAGE mediates amyloid-beta peptide transport across the blood–brain barrier and accumulation in brain. Nat Med 9:907–913. doi: 10.1038/nm890 PubMedGoogle Scholar
  164. 164.
    Kumar-Singh S, Pirici D, McGowan E, Serneels S, Ceuterick C, Hardy J, Duff K, Dickson D, Van Broeckhoven C (2005) Dense-core plaques in Tg2576 and PSAPP mouse models of Alzheimer’s disease are centered on vessel walls. Am J Pathol 167:527–543. doi: 10.1016/S0002-9440(10)62995-1 PubMedPubMedCentralGoogle Scholar
  165. 165.
    Paul J, Strickland S, Melchor JP (2007) Fibrin deposition accelerates neurovascular damage and neuroinflammation in mouse models of Alzheimer’s disease. J Exp Med 204:1999–2008. doi: 10.1084/jem.20070304 PubMedPubMedCentralGoogle Scholar
  166. 166.
    Dickstein DL, Biron KE, Ujiie M, Pfeifer CG, Jeffries AR, Jefferies WA (2006) Abeta peptide immunization restores blood–brain barrier integrity in Alzheimer disease. FASEB J 20:426–433. doi: 10.1096/fj.05-3956com PubMedGoogle Scholar
  167. 167.
    Zhong Z, Deane R, Ali Z, Parisi M, Shapovalov Y, O’Banion MK, Stojanovic K, Sagare A, Boillee S, Cleveland DW, Zlokovic BV (2008) ALS-causing SOD1 mutants generate vascular changes prior to motor neuron degeneration. Nat Neurosci 11:420–422. doi: 10.1038/nn2073 PubMedPubMedCentralGoogle Scholar
  168. 168.
    Larochelle C, Alvarez JI, Prat A (2011) How do immune cells overcome the blood–brain barrier in multiple sclerosis? FEBS Lett 585:3770–3780. doi: 10.1016/j.febslet.2011.04.066 PubMedGoogle Scholar
  169. 169.
    McCormack PL (2013) Natalizumab: a review of its use in the management of relapsing-remitting multiple sclerosis. Drugs 73:1463–1481. doi: 10.1007/s40265-013-0102-7 PubMedGoogle Scholar
  170. 170.
    Guttmacher AE, Marchuk DA, White RI Jr (1995) Hereditary hemorrhagic telangiectasia. N Engl J Med 333:918–924. doi: 10.1056/NEJM199510053331407 PubMedGoogle Scholar
  171. 171.
    da Costa L, Wallace MC, Ter Brugge KG, O’Kelly C, Willinsky RA, Tymianski M (2009) The natural history and predictive features of hemorrhage from brain arteriovenous malformations. Stroke 40:100–105. doi: 10.1161/STROKEAHA.108.524678 PubMedGoogle Scholar
  172. 172.
    Kim H, Marchuk DA, Pawlikowska L, Chen Y, Su H, Yang GY, Young WL (2008) Genetic considerations relevant to intracranial hemorrhage and brain arteriovenous malformations. Acta Neurochir Suppl 105:199–206PubMedPubMedCentralGoogle Scholar
  173. 173.
    ten Dijke P, Arthur HM (2007) Extracellular control of TGFbeta signalling in vascular development and disease. Nat Rev Mol Cell Biol 8:857–869. doi: 10.1038/nrm2262 PubMedGoogle Scholar
  174. 174.
    Bayrak-Toydemir P, McDonald J, Markewitz B, Lewin S, Miller F, Chou LS, Gedge F, Tang W, Coon H, Mao R (2006) Genotype-phenotype correlation in hereditary hemorrhagic telangiectasia: mutations and manifestations. Am J Med Genet A 140:463–470. doi: 10.1002/ajmg.a.31101 PubMedGoogle Scholar
  175. 175.
    Lesca G, Genin E, Blachier C, Olivieri C, Coulet F, Brunet G, Dupuis-Girod S, Buscarini E, Soubrier F, Calender A, Danesino C, Giraud S, Plauchu H (2008) Hereditary hemorrhagic telangiectasia: evidence for regional founder effects of ACVRL1 mutations in French and Italian patients. Eur J Hum Genet 16:742–749. doi: 10.1038/ejhg.2008.3 PubMedGoogle Scholar
  176. 176.
    Letteboer TG, Zewald RA, Kamping EJ, de Haas G, Mager JJ, Snijder RJ, Lindhout D, Hennekam FA, Westermann CJ, van Ploos Amstel JK (2005) Hereditary hemorrhagic telangiectasia: ENG and ALK-1 mutations in Dutch patients. Hum Genet 116:8–16. doi: 10.1007/s00439-004-1196-5 PubMedGoogle Scholar
  177. 177.
    McDonald J, Bayrak-Toydemir P, Pyeritz RE (2011) Hereditary hemorrhagic telangiectasia: an overview of diagnosis, management, and pathogenesis. Genet Med 13:607–616. doi: 10.1097/GIM.0b013e3182136d32 PubMedGoogle Scholar
  178. 178.
    Saba HI, Morelli GA, Logrono LA (1994) Brief report: treatment of bleeding in hereditary hemorrhagic telangiectasia with aminocaproic acid. N Engl J Med 330:1789–1790. doi: 10.1056/NEJM199406233302504 PubMedGoogle Scholar
  179. 179.
    McAllister KA, Grogg KM, Johnson DW, Gallione CJ, Baldwin MA, Jackson CE, Helmbold EA, Markel DS, McKinnon WC, Murrell J et al (1994) Endoglin, a TGF-beta binding protein of endothelial cells, is the gene for hereditary haemorrhagic telangiectasia type 1. Nat Genet 8:345–351. doi: 10.1038/ng1294-345 PubMedGoogle Scholar
  180. 180.
    Johnson DW, Berg JN, Baldwin MA, Gallione CJ, Marondel I, Yoon SJ, Stenzel TT, Speer M, Pericak-Vance MA, Diamond A, Guttmacher AE, Jackson CE, Attisano L, Kucherlapati R, Porteous ME, Marchuk DA (1996) Mutations in the activin receptor-like kinase 1 gene in hereditary haemorrhagic telangiectasia type 2. Nat Genet 13:189–195. doi: 10.1038/ng0696-189 PubMedGoogle Scholar
  181. 181.
    Gougos A, Letarte M (1990) Primary structure of endoglin, an RGD-containing glycoprotein of human endothelial cells. J Biol Chem 265:8361–8364PubMedGoogle Scholar
  182. 182.
    ten Dijke P, Goumans MJ, Pardali E (2008) Endoglin in angiogenesis and vascular diseases. Angiogenesis 11:79–89. doi: 10.1007/s10456-008-9101-9 PubMedGoogle Scholar
  183. 183.
    Barbara NP, Wrana JL, Letarte M (1999) Endoglin is an accessory protein that interacts with the signaling receptor complex of multiple members of the transforming growth factor-beta superfamily. J Biol Chem 274:584–594PubMedGoogle Scholar
  184. 184.
    Vincent P, Plauchu H, Hazan J, Faure S, Weissenbach J, Godet J (1995) A third locus for hereditary haemorrhagic telangiectasia maps to chromosome 12q. Hum Mol Genet 4:945–949PubMedGoogle Scholar
  185. 185.
    Johnson DW, Berg JN, Gallione CJ, McAllister KA, Warner JP, Helmbold EA, Markel DS, Jackson CE, Porteous ME, Marchuk DA (1995) A second locus for hereditary hemorrhagic telangiectasia maps to chromosome 12. Genome Res 5:21–28PubMedGoogle Scholar
  186. 186.
    Gallione CJ, Repetto GM, Legius E, Rustgi AK, Schelley SL, Tejpar S, Mitchell G, Drouin E, Westermann CJ, Marchuk DA (2004) A combined syndrome of juvenile polyposis and hereditary haemorrhagic telangiectasia associated with mutations in MADH4 (SMAD4). Lancet 363:852–859. doi: 10.1016/S0140-6736(04)15732-2 PubMedGoogle Scholar
  187. 187.
    Park SO, Wankhede M, Lee YJ, Choi EJ, Fliess N, Choe SW, Oh SH, Walter G, Raizada MK, Sorg BS, Oh SP (2009) Real-time imaging of de novo arteriovenous malformation in a mouse model of hereditary hemorrhagic telangiectasia. J Clin Invest 119:3487–3496. doi: 10.1172/JCI39482 PubMedPubMedCentralGoogle Scholar
  188. 188.
    Roman BL, Pham VN, Lawson ND, Kulik M, Childs S, Lekven AC, Garrity DM, Moon RT, Fishman MC, Lechleider RJ, Weinstein BM (2002) Disruption of acvrl1 increases endothelial cell number in zebrafish cranial vessels. Development 129:3009–3019PubMedGoogle Scholar
  189. 189.
    Sorensen LK, Brooke BS, Li DY, Urness LD (2003) Loss of distinct arterial and venous boundaries in mice lacking endoglin, a vascular-specific TGFbeta coreceptor. Dev Biol 261:235–250PubMedGoogle Scholar
  190. 190.
    Mahmoud M, Allinson KR, Zhai Z, Oakenfull R, Ghandi P, Adams RH, Fruttiger M, Arthur HM (2010) Pathogenesis of arteriovenous malformations in the absence of endoglin. Circ Res 106:1425–1433. doi: 10.1161/CIRCRESAHA.109.211037 PubMedGoogle Scholar
  191. 191.
    Mancini ML, Terzic A, Conley BA, Oxburgh LH, Nicola T, Vary CP (2009) Endoglin plays distinct roles in vascular smooth muscle cell recruitment and regulation of arteriovenous identity during angiogenesis. Dev Dyn 238:2479–2493. doi: 10.1002/dvdy.22066 PubMedPubMedCentralGoogle Scholar
  192. 192.
    Kovacs Z, Ikezaki K, Samoto K, Inamura T, Fukui M (1996) VEGF and flt. Expression time kinetics in rat brain infarct. Stroke 27:1865–1872 (Discussion 1872–1863)PubMedGoogle Scholar
  193. 193.
    Hayashi T, Abe K, Suzuki H, Itoyama Y (1997) Rapid induction of vascular endothelial growth factor gene expression after transient middle cerebral artery occlusion in rats. Stroke 28:2039–2044PubMedGoogle Scholar
  194. 194.
    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
  195. 195.
    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 57:874–882PubMedGoogle Scholar
  196. 196.
    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 265:107–110PubMedGoogle Scholar
  197. 197.
    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 58:654–666PubMedGoogle Scholar
  198. 198.
    Issa R, Krupinski J, Bujny T, Kumar S, Kaluza J, Kumar P (1999) Vascular endothelial growth factor and its receptor, KDR, in human brain tissue after ischemic stroke. Lab Invest 79:417–425PubMedGoogle Scholar
  199. 199.
    Slevin M, Krupinski J, Slowik A, Kumar P, Szczudlik A, Gaffney J (2000) Serial measurement of vascular endothelial growth factor and transforming growth factor-beta1 in serum of patients with acute ischemic stroke. Stroke 31:1863–1870PubMedGoogle Scholar
  200. 200.
    Gunsilius E, Petzer AL, Stockhammer G, Kahler CM, Gastl G (2001) Serial measurement of vascular endothelial growth factor and transforming growth factor-beta1 in serum of patients with acute ischemic stroke. Stroke 32:275–278PubMedGoogle Scholar
  201. 201.
    Beck H, Acker T, Puschel AW, Fujisawa H, Carmeliet P, Plate KH (2002) Cell type-specific expression of neuropilins in an MCA-occlusion model in mice suggests a potential role in post-ischemic brain remodeling. J Neuropathol Exp Neurol 61:339–350PubMedGoogle Scholar
  202. 202.
    Zhang ZG, Tsang W, Zhang L, Powers C, Chopp M (2001) Up-regulation of neuropilin-1 in neovasculature after focal cerebral ischemia in the adult rat. J Cereb Blood Flow Metab 21:541–549. doi: 10.1097/00004647-200105000-00008 PubMedGoogle Scholar
  203. 203.
    Lin TN, Wang CK, Cheung WM, Hsu CY (2000) Induction of angiopoietin and Tie receptor mRNA expression after cerebral ischemia-reperfusion. J Cereb Blood Flow Metab 20:387–395. doi: 10.1097/00004647-200002000-00021 PubMedGoogle Scholar
  204. 204.
    Zhang Z, Chopp M (2002) Vascular endothelial growth factor and angiopoietins in focal cerebral ischemia. Trends Cardiovasc Med 12:62–66PubMedGoogle Scholar
  205. 205.
    Zhang ZG, Chopp M, Lu D, Wayne T, Zhang RL, Morris D (1999) Receptor tyrosine kinase tie 1 mRNA is upregulated on cerebral microvessels after embolic middle cerebral artery occlusion in rat. Brain Res 847:338–342PubMedGoogle Scholar
  206. 206.
    Lin TN, Nian GM, Chen SF, Cheung WM, Chang C, Lin WC, Hsu CY (2001) Induction of Tie-1 and Tie-2 receptor protein expression after cerebral ischemia-reperfusion. J Cereb Blood Flow Metab 21:690–701. doi: 10.1097/00004647-200106000-00007 PubMedGoogle Scholar
  207. 207.
    Iihara K, Sasahara M, Hashimoto N, Uemura Y, Kikuchi H, Hazama F (1994) Ischemia induces the expression of the platelet-derived growth factor-B chain in neurons and brain macrophages in vivo. J Cereb Blood Flow Metab 14:818–824. doi: 10.1038/jcbfm.1994.102 PubMedGoogle Scholar
  208. 208.
    Krupinski J, Issa R, Bujny T, Slevin M, Kumar P, Kumar S, Kaluza J (1997) A putative role for platelet-derived growth factor in angiogenesis and neuroprotection after ischemic stroke in humans. Stroke 28:564–573PubMedGoogle Scholar
  209. 209.
    Renner O, Tsimpas A, Kostin S, Valable S, Petit E, Schaper W, Marti HH (2003) Time- and cell type-specific induction of platelet-derived growth factor receptor-beta during cerebral ischemia. Brain Res Mol Brain Res 113:44–51PubMedGoogle Scholar
  210. 210.
    Bernaudin M, Marti HH, Roussel S, Divoux D, Nouvelot A, MacKenzie ET, Petit E (1999) A potential role for erythropoietin in focal permanent cerebral ischemia in mice. J Cereb Blood Flow Metab 19:643–651. doi: 10.1097/00004647-199906000-00007 PubMedGoogle Scholar
  211. 211.
    Veltkamp R, Rajapakse N, Robins G, Puskar M, Shimizu K, Busija D (2002) Transient focal ischemia increases endothelial nitric oxide synthase in cerebral blood vessels. Stroke 33:2704–2710PubMedGoogle Scholar
  212. 212.
    Wiessner C, Gehrmann J, Lindholm D, Topper R, Kreutzberg GW, Hossmann KA (1993) Expression of transforming growth factor-beta 1 and interleukin-1 beta mRNA in rat brain following transient forebrain ischemia. Acta Neuropathol 86:439–446PubMedGoogle Scholar
  213. 213.
    Krupinski J, Kumar P, Kumar S, Kaluza J (1996) Increased expression of TGF-beta 1 in brain tissue after ischemic stroke in humans. Stroke 27:852–857PubMedGoogle Scholar
  214. 214.
    Yamashita K, Gerken U, Vogel P, Hossmann K, Wiessner C (1999) Biphasic expression of TGF-beta1 mRNA in the rat brain following permanent occlusion of the middle cerebral artery. Brain Res 836:139–145PubMedGoogle Scholar
  215. 215.
    Haqqani AS, Nesic M, Preston E, Baumann E, Kelly J, Stanimirovic D (2005) Characterization of vascular protein expression patterns in cerebral ischemia/reperfusion using laser capture microdissection and ICAT-nanoLC-MS/MS. FASEB J 19:1809–1821. doi: 10.1096/fj.05-3793com PubMedGoogle Scholar
  216. 216.
    Chen HH, Chien CH, Liu HM (1994) Correlation between angiogenesis and basic fibroblast growth factor expression in experimental brain infarct. Stroke 25:1651–1657PubMedGoogle Scholar
  217. 217.
    Hara Y, Tooyama I, Yasuhara O, Akiyama H, McGeer PL, Handa J, Kimura H (1994) Acidic fibroblast growth factor-like immunoreactivity in rat brain following cerebral infarction. Brain Res 664:101–107PubMedGoogle Scholar
  218. 218.
    Lin TN, Te J, Lee M, Sun GY, Hsu CY (1997) Induction of basic fibroblast growth factor (bFGF) expression following focal cerebral ischemia. Brain Res Mol Brain Res 49:255–265PubMedGoogle Scholar
  219. 219.
    Issa R, AlQteishat A, Mitsios N, Saka M, Krupinski J, Tarkowski E, Gaffney J, Slevin M, Kumar S, Kumar P (2005) Expression of basic fibroblast growth factor mRNA and protein in the human brain following ischaemic stroke. Angiogenesis 8:53–62. doi: 10.1007/s10456-005-5613-8 PubMedGoogle Scholar

Copyright information

© Springer Basel 2014

Authors and Affiliations

  • Mario Vallon
    • 1
  • Junlei Chang
    • 1
  • Haijing Zhang
    • 1
  • Calvin J. Kuo
    • 1
    Email author
  1. 1.Division of HematologyStanford University School of MedicineStanfordUSA

Personalised recommendations