Mechanisms of Angiogenesis pp 163-180

Part of the Experientia Supplementum book series (EXS)

Angiogenesis — a self-adapting principle in hypoxia

  • Hugo H. Marti


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  1. 1.
    Dor Y, Djonov V, Keshet E (2003) Making vascular networks in the adult: Branching morphogenesis without a roadmap. Trends Cell Biol 13: 131–136PubMedCrossRefGoogle Scholar
  2. 2.
    Black JE, Sirevaag AM, Greenough WT (1987) Complex experience promotes capillary formation in young rat visual cortex. Neurosci Lett 83: 351–355PubMedCrossRefGoogle Scholar
  3. 3.
    Shaul PW, North AJ, Brannon TS, Ujiie K, Wells LB, Nisen PA, Lowenstein CJ, Snyder SH, Star RA (1995) Prolonged in vivo hypoxia enhances nitric oxide synthase type I and type III gene expression in adult rat lung. Am J Resp Cell Mol Biol 13: 167–174Google Scholar
  4. 4.
    Melillo G, Musso T, Sica A, Taylor LS, Cox GW, Varesio L (1995) A hypoxia-responsive element mediates a novel pathway of activation of the inducible nitric oxide synthase promoter. J Exp Med 182: 1683–1693PubMedCrossRefGoogle Scholar
  5. 5.
    Coulet F, Nadaud S, Agrapart M, Soubrier F (2003) Identification of hypoxia-response element in the human endothelial nitric-oxide synthase gene promoter. J Biol Chem 278: 46230–46240PubMedCrossRefGoogle Scholar
  6. 6.
    Semenza GL (2001) HIF-1, O2, and the 3 PHDs: how animal cells signal hypoxia to the nucleus. Cell 107: 1–3PubMedCrossRefGoogle Scholar
  7. 7.
    Wenger RH (2002) Cellular adaptation to hypoxia: O2-sensing protein hydroxylases, hypoxiainducible transcription factors, and O2-regulated gene expression. FASEB J 16: 1151–1162PubMedCrossRefGoogle Scholar
  8. 8.
    Tian H, McKnight SL, Russell DW (1997) Endothelial pas domain protein 1 (EPAS1), a transcription factor selectively expressed in endothelial cells. Gene Dev 11: 72–82PubMedGoogle Scholar
  9. 9.
    Wiesener MS, Turley H, Allen WE, Willam C, Eckardt K-U, Talks KL, Wood SM, Gatter KC, Harris AL, Pugh CW et al. (1998) Induction of endothelial PAS domain protein-1 by hypoxia: characterization and comparison with hypoxia-inducible factor-1-á. Blood 92: 2260–2268PubMedGoogle Scholar
  10. 10.
    Flamme I, Fröhlich T, von Reutern M, Kappel A, Damert A, Risau W (1997) HRF, a putative basic helix-loop-helix-PAS-domain transcription factor is closely related to hypoxia-inducible factor-1α and developmentally expressed in blood vessels. Mech Develop 63: 51–60CrossRefGoogle Scholar
  11. 11.
    Ema M, Taya S, Yokotani N, Sogawa K, Matsuda Y, Fujii-Kuriyama Y (1997) A novel bHLH-PAS factor with close sequence similarity to hypoxia-inducible factor 1α regulates the VEGF expression and is potentially involved in lung and vascular development. Proc Natl Acad Sci USA 94: 4273–4278PubMedCrossRefGoogle Scholar
  12. 12.
    Makino Y, Cao R, Svensson K, Bertilsson G, Åsman M, Tanaka H, Cao Y, Berkenstam A, Poellinger L (2001) Inhibitory PAS domain protein is a negative regulator of hypoxia-inducible gene expression. Nature 414: 550–554PubMedCrossRefGoogle Scholar
  13. 13.
    Semenza GL (2000) HIF-1 and human disease: One highly involved factor. Gene Dev 14: 1983–1991PubMedGoogle Scholar
  14. 14.
    Jiang BH, Semenza GL, Bauer C, Marti HH (1996) Hypoxia-inducible factor 1 levels vary exponentially over a physiologically relevant range of O2 tension. Am J Physiol 271: C1172–C1180PubMedGoogle Scholar
  15. 15.
    Wenger RH, Rolfs A, Marti HH, Guénet J-L, Gassmann M (1996) Nucleotide sequence, chromosomal assignment and mRNA expression of mouse hypoxia-inducible factor-1α. Biochem Biophys Res Commun 223: 54–59PubMedCrossRefGoogle Scholar
  16. 16.
    Jewell UR, Kvietikova I, Scheid A, Bauer C, Wenger RH, Gassmann M (2001) Induction of HIF-1α in response to hypoxia is instantaneous. FASEB J 15: 1312–1314PubMedGoogle Scholar
  17. 17.
    Maxwell PH, Wiesener MS, Chang GW, Clifford SC, Vaux EC, Cockman ME, Wykoff CC, Pugh CW, Maher ER, Ratcliffe PJ (1999) The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis. Nature 399: 271–275PubMedCrossRefGoogle Scholar
  18. 18.
    Talks KL, Turley H, Gatter KC, Maxwell PH, Pugh CW, Ratcliffe PJ, Harris AL (2000) The expression and distribution of the hypoxia-inducible factors HIF-1α and HIF-2β in normal human tissues, cancers, and tumor-associated macrophages. Am J Pathol 157: 411–421PubMedGoogle Scholar
  19. 19.
    Bergeron M, Yu AY, Solway KE, Semenza GL, Sharp FR (1999) Induction of hypoxia-inducible factor-1 (HIF-1) and its target genes following focal ischaemia in rat brain. Eur J Neurosci 11: 4159–4170PubMedCrossRefGoogle Scholar
  20. 20.
    Chavez JC, Agani F, Pichiule P, LaManna JC (2000) Expression of hypoxia-inducible factor-1α in the brain of rats during chronic hypoxia. J Appl Physiol 89: 1937–1942PubMedGoogle Scholar
  21. 21.
    Ivan M, Kondo K, Yang HF, Kim W, Valiando J, Ohh M, Salic A, Asara JM, Lane WS, Kaelin WG (2001) HIFá targeted for VHL-mediated destruction by proline hydroxylation: Implications for O2 sensing. Science 292: 464–468PubMedGoogle Scholar
  22. 22.
    Jaakkola P, Mole DR, Tian YM, Wilson MI, Gielbert J, Gaskell SJ, von Kriegsheim A, Hebestrei HF, Mukherji M, Schofield CJ et al. (2001) Targeting of HIFα to the von Hippel-Lindau ubiquitylation complex by O2-regulated prolyl hydroxylation. Science 292: 468–472PubMedGoogle Scholar
  23. 23.
    Epstein AC, Gleadle JM, McNeill LA, Hewitson KS, O’Rourke J, Mole DR, Mukherji M, Metzen E, Wilson MI, Dhanda A et al. (2001) C. elegans EGL-9 and mammalian homologs define a family of dioxygenases that regulate HIF by prolyl hydroxylation. Cell 107: 43–54PubMedCrossRefGoogle Scholar
  24. 24.
    Bruick RK, McKnight SL (2001) A conserved family of prolyl-4-hydroxylases that modify HIF. Science 294: 1337–1340PubMedCrossRefGoogle Scholar
  25. 25.
    Masson N, Ratcliffe PJ (2003) HIF prolyl and asparaginyl hyroxylases in the biological response to intracellular O2 levels. J Cell Sci 116: 3041–3049PubMedCrossRefGoogle Scholar
  26. 26.
    Lando D, Gorman JJ, Whitelaw ML, Peet DJ (2003) Oxygen-dependent regulation of hypoxiainducible factors by prolyl and asparaginyl hydroxylation. Eur J Biochem 270: 781–790PubMedCrossRefGoogle Scholar
  27. 27.
    Lando D, Peet DJ, Whelan DA, Gorman JJ, Whitelaw ML (2002) Asparagine hydroxylation of the HIF transactivation domain: a hypoxic switch. Science 295: 858–861PubMedCrossRefGoogle Scholar
  28. 28.
    Lando D, Peet DJ, Gorman JJ, Whelan DA, Whitelaw ML, Bruick RK (2002) FIH-1 is an asparaginyl hydroxylase enzyme that regulates the transcriptional activity of hypoxia-inducible factor. Gene Dev 16: 1466–1471PubMedCrossRefGoogle Scholar
  29. 29.
    Hewitson KS, McNeill LA, Riordan MV, Tian YM, Bullock AN, Welford RW, Elkins JM, Oldha NJ, Bhattacharya S, Gleadle JM et al. (2002) Hypoxia-inducible factor (HIF) asparagine hydroxylase is identical to factor inhibiting HIF (FIH) and is related to the cupin structural family. J Biol Chem 277: 26351–26355PubMedCrossRefGoogle Scholar
  30. 30.
    Pugh CW, Ratcliffe PJ (2003) Regulation of angiogenesis by hypoxia: role of the HIF system. Nat Med 9: 677–684PubMedCrossRefGoogle Scholar
  31. 31.
    Risau W (1997) Mechanisms of angiogenesis. Nature 386: 671–674PubMedCrossRefGoogle Scholar
  32. 32.
    Ferrara N, Davis-Smyth T (1997) The biology of vascular endothelial growth factor. Endocr Rev 18: 4–25PubMedCrossRefGoogle Scholar
  33. 33.
    Robinson CJ, Stringer SE (2001) The splice variants of vascular endothelial growth factor (VEGF) and their receptors. J Cell Sci 114: 853–865PubMedGoogle Scholar
  34. 34.
    Marti HH, Risau W (1998) Systemic hypoxia changes the organ-specific distribution of vascular endothelial growth factor and its receptors. Proc Natl Acad Sci USA 95: 15809–15814PubMedCrossRefGoogle Scholar
  35. 35.
    Soker S, Takashima S, Miao HQ, Neufeld G, Klagsbrun M (1998) Neuropilin-1 is expressed by endothelial and tumor cells as an isoform-specific receptor for vascular endothelial growth factor. Cell 92: 735–745PubMedCrossRefGoogle Scholar
  36. 36.
    Gluzman-Poltorak Z, Cohen T, Herzog Y, Neufeld G (2000) Neuropilin-2 is a receptor for the vascular endothelial growth factor (VEGF) forms VEGF-145 and VEGF-165. J Biol Chem 275: 18040–18045PubMedCrossRefGoogle Scholar
  37. 37.
    Shweiki D, Itin A, Soffer D, Keshet E (1992) Vascular endothelial growth factor induced by hypoxia may mediate hypoxia-initiated angiogenesis. Nature 359: 843–845PubMedCrossRefGoogle Scholar
  38. 38.
    Plate KH, Breier G, Weich HA, Risau W (1992) Vascular endothelial growth factor is a potential tumour angiogenesis factor in human gliomas in vivo. Nature 359: 845–848PubMedCrossRefGoogle Scholar
  39. 39.
    Forsythe JA, Jiang B-H, Iyer NV, Agani F, Leung SW, Koos RD, Semenza GL (1996) Activation of vascular endothelial growth factor gene transcription by hypoxia-inducible factor 1. Mol Cell Biol 16: 4604–4613PubMedGoogle Scholar
  40. 40.
    Ikeda E, Achen MG, Breier G, Risau W (1995) Hypoxia-induced transcriptional activation and increased mRNA stability of vascular endothelial growth factor (VEGF) in C6 glioma cells. J Biol Chem 270: 19761–19766PubMedCrossRefGoogle Scholar
  41. 41.
    Stein I, Itin A, Einat P, Skaliter R, Grossman Z, Keshet E (1998) Translation of vascular endothelial growth factor mRNA by internal ribosome entry: Implications for translation under hypoxia. Mol Cell Biol 18: 3112–3119PubMedGoogle Scholar
  42. 42.
    Tuder RM, Flook BE, Voelkel NF (1995) Increased gene expression for VEGF and the VEGF receptors KDR/flk and flt in lungs exposed to acute or chronic hypoxia, Modulation of gene expression by nitric oxide. J Clin Invest 95: 1798–1807PubMedGoogle Scholar
  43. 43.
    Marti HJH, Bernaudin M, Bellail A, Schoch H, Euler M, Petit E, Risau W (2000) Hypoxiainduced vascular endothelial growth factor expression precedes neovascularization after cerebral ischemia. Am J Pathol 156: 965–976PubMedGoogle Scholar
  44. 44.
    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: 713–717PubMedCrossRefGoogle Scholar
  45. 45.
    Gerber H-P, Condorelli F, Park J, Ferrara N (1997) Differential transcriptional regulation of the two vascular endothelial growth factor receptor genes; flt-1, but not flk-1/KDR, is up-regulated by hypoxia. J Biol Chem 272: 23659–23667PubMedCrossRefGoogle Scholar
  46. 46.
    Elvert G, Kappel A, Heidenreich R, Englmeier U, Lanz S, Acker T, Rauter M, Plate K, Siewek M, Breier G, Flamme I (2003) Cooperative interaction of hypoxia-inducible factor-2α (HIF-2α) and Ets-1 in the transcriptional activation of vascular endothelial growth factor receptor-2 (Flk-1). J Biol Chem 278: 7520–7530PubMedCrossRefGoogle Scholar
  47. 47.
    Li J, Brown LF, Hibberd MG, Grossman JD, Morgan JP, Simons M (1996) VEGF, flk-1, and flt-1 expression in a rat myocardial infarction model of angiogenesis. Am J Physiol 270: H1803–H1811PubMedGoogle Scholar
  48. 48.
    Kremer C, Breier G, Risau W, Plate KH (1997) Up-regulation of flk-1/vascular endothelial growth factor receptor 2 by its ligand in a cerebral slice culture system. Cancer Res 57: 3852–3859PubMedGoogle Scholar
  49. 49.
    Shen B-Q, Lee DY, Gerber H-P, Keyt BA, Ferrara N, Zioncheck TF (1998) Homologous up-regulation of KDR/Flk-1 receptor expression by vascular endothelial growth factor in vitro. J Biol Chem 273: 29979–29985PubMedCrossRefGoogle Scholar
  50. 50.
    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: 541–549PubMedCrossRefGoogle Scholar
  51. 51.
    Carmeliet P (2003) Angiogenesis in health and disease. Nat Med 9: 653–660PubMedCrossRefGoogle Scholar
  52. 52.
    Jones N, Iljin K, Dumont DJ, Alitalo K (2001) Tie receptors: New modulators of angiogenic and lymphangiogenic responses. Nature Rev Mol Cell Biol 2: 257–267CrossRefGoogle Scholar
  53. 53.
    Holash J, Wiegand SJ, Yancopoulos GD (1999) New model of tumor angiogenesis: dynamic balance between vessel regression and growth mediated by angiopoietins and VEGF. Oncogene 18: 5356–5362PubMedCrossRefGoogle Scholar
  54. 54.
    Mandriota SJ, Pepper MS (1998) Regulation of angiopoietin-2 mRNA levels in bovine microvasculal endothelial cells by cytokines and hypoxia. Circ Res 83: 852–859PubMedGoogle Scholar
  55. 55.
    Yuan HT, Yang SP, Woolf AS (2000) Hypoxia up-regulates angiopoietin-2, a Tie-2 ligand, in mouse mesangial cells. Kidney Int 58: 1912–1919PubMedCrossRefGoogle Scholar
  56. 56.
    Park YS, Kim NH, Jo I (2003) Hypoxia and vascular endothelial growth factor acutely up-regulate angiopoietin-1 and Tie2 mRNA in bovine retinal pericytes. Microvasc Res 65: 125–131PubMedCrossRefGoogle Scholar
  57. 57.
    Krikun G, Schatz F, Finlay T, Kadner S, Mesia A, Gerrets R, Lockwood CJ (2000) Expression of angiopoietin-2 by human endometrial endothelial cells: regulation by hypoxia and inflammation. Biochem Biophys Res Commun 275: 159–163PubMedCrossRefGoogle Scholar
  58. 58.
    Enholm B, Paavonen K, Ristimaki A, Kumar V, Gunji Y, Klefstrom J, Kivinen L, Laiho M, Olofsson B, Joukov V et al. (1997) Comparison of VEGF, VEGF-B, VEGF-C and Ang-1 m-RNA regulation by serum, growth factors, oncoproteins and hypoxia. Oncogene 14: 2475–2483PubMedCrossRefGoogle Scholar
  59. 59.
    Yamakawa M, Liu LX, Date T, Belanger AJ, Vincent KA, Akita GY, Kuriyama T, Cheng SH, Gregory RJ, Jiang C (2003) Hypoxia-inducible factor-1 mediates activation of cultured vascular endothelial cells by inducing multiple angiogenic factors. Circ Res 93: 664–673PubMedCrossRefGoogle Scholar
  60. 60.
    Willam C, Koehne P, Jürgensen JS, Gräfe M, Wagner KD, Bachmann S, Frei U, Eckardt KU (2000) Tie2 receptor expression is stimulated by hypoxia and proinflammatory cytokines in human endothelial cells. Circ Res 87: 370–377PubMedGoogle Scholar
  61. 61.
    Christensen RA, Fujikawa K, Madore R, Oettgen P, Varticovski L (2002) NERF2, a member of the Ets family of transcription factors, is increased in response to hypoxia and angiopoietin-1: A potential mechanism for Tie2 regulation during hypoxia. J Cell Biochem 85: 505–515PubMedCrossRefGoogle Scholar
  62. 62.
    Oh H, Takagi H, Suzuma K, Otani A, Matsumura M, Honda Y (1999) Hypoxia and vascular endothelial growth factor selectively up-regulate angiopoietin-2 in bovine microvascular endothelial cells. J Biol Chem 274: 15732–15739PubMedCrossRefGoogle Scholar
  63. 63.
    Pichiule P, LaManna JC (2002) Angiopoietin-2 and rat brain capillary remodeling during adaptation and deadaptation to prolonged mild hypoxia. J Appl Physiol 93: 1131–1139PubMedGoogle Scholar
  64. 64.
    Abdulmalek K, Ashur F, Ezer N, Ye F, Magder S, Hussain SNA (2001) Differential expression of Tie-2 receptors and angiopoietins in response to in vivo hypoxia in rats. Am J Physiol 281: L582–L590Google Scholar
  65. 65.
    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 Pathol157: 1473–1483PubMedGoogle Scholar
  66. 66.
    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: 387–395PubMedCrossRefGoogle Scholar
  67. 67.
    Kelly BD, Hackett SF, Hirota K, Oshima Y, Cai Z, Berg-Dixon S, Rowan A, Yan Z, Campochiar PA, Semenza GL (2003) Cell type-specific regulation of angiogenic growth factor gene expression and induction of angiogenesis in nonischemic tissue by a constitutively active form of hypoxiainducible factor 1. Circ Res 93: 1074–1081PubMedCrossRefGoogle Scholar
  68. 68.
    Heldin CH, Westermark B (1999) Mechanism of action and in vivo role of platelet-derived growth factor. Physiol Rev 79: 1283–1316PubMedGoogle Scholar
  69. 69.
    Li X, Ponten A, Aase K, Karlsson L, Abramsson A, Uutela M, Bäckström G, Hellström M, Boström H et al. (2000) PDGF-C is a new protease-activated ligand for the PDGF á-receptor. Nature Cell Biol 2: 302–309PubMedCrossRefGoogle Scholar
  70. 70.
    Bergsten E, Uutela M, Li X, Pietras K, Ostman A, Heldin CH, Alitalo K, Eriksson U (2001) PDGF-D is a specific, protease-activated ligand for the PDGF â-receptor. Nature Cell Biol 3: 512–516PubMedCrossRefGoogle Scholar
  71. 71.
    Lindahl P, Johansson BR, Levéen P, Betsholtz C (1997) Pericyte loss and microaneurysm formation in PDGF-B-deficient mice. Science 277: 242–245PubMedCrossRefGoogle Scholar
  72. 72.
    Hellström M, Kalén M, Lindahl P, Abramsson A, Betsholtz C (1999) Role of PDGF-B and PDGFR-â in recruitment of vascular smooth muscle cells and pericytes during embryonic blood vessel formation in the mouse. Development 126: 3047–3055PubMedGoogle Scholar
  73. 73.
    Kourembanas S, Hannan RL, Faller DV (1990) Oxygen tension regulates the expression of the platelet-derived growth factor-B chain gene in human endothelial cells. J Clin Invest 86: 670–674PubMedCrossRefGoogle Scholar
  74. 74.
    Kuwabara K, Ogawa S, Matsumoto M, Koga S, Clauss M, Pinsky DJ, Lyn P, Leavy J, Witte L, Joseph-Silverstein J et al. (1995) Hypoxia-mediated induction of acidic/basic fibroblast growth factor and platelet-derived growth factor in mononuclear phagocytes stimulates growth of hypoxic endothelial cells. Proc Natl Acad Sci USA 92: 4606–4610PubMedCrossRefGoogle Scholar
  75. 75.
    Zhang SXL, Gozal D, Sachleben LR Jr Rane M, Klein JB, Gozal E (2003) Hypoxia induces an autocrine-paracrine survival pathway via platelet-derived growth factor (PDGF)-B/PDGF-â receptor/phosphatidylinositol 3-kinase/Akt signaling in RN46A neuronal cells. FASEB J 17: 1709–1711PubMedGoogle Scholar
  76. 76.
    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-â during cerebral ischemia. Brain Res Mol Brain Res 113: 44–51PubMedCrossRefGoogle Scholar
  77. 77.
    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
  78. 78.
    Felmeden DC, Blann AD, Lip GY (2003) Angiogenesis: Basic pathophysiology and implications for disease. Eur Heart J 24: 586–603PubMedCrossRefGoogle Scholar
  79. 79.
    Gale NW, Yancopoulos GD (1999) Growth factors acting via endothelial cell-specific receptor tyrosine kinases: VEGFs, angiopoietins, and ephrins in vascular development. Gene Dev 13: 1055–1066PubMedGoogle Scholar
  80. 80.
    Carmeliet P (2000) Mechanisms of angiogenesis and arteriogenesis. Nat Med 6: 389–395PubMedCrossRefGoogle Scholar
  81. 81.
    Jain RK (2003) Molecular regulation of vessel maturation. Nat Med 9: 685–693PubMedCrossRefGoogle Scholar
  82. 82.
    Ribatti D, Vacca A, Roccaro AM, Crivellato E, Presta M (2003) Erythropoietin as an angiogenic factor. Eur J Clin Invest 33: 891–896PubMedCrossRefGoogle Scholar
  83. 83.
    Marti HH, Bernaudin M, Petit E, Bauer C (2000) Neuroprotection and angiogenesis: A dual role of erythropoietin in brain ischemia. News Physiol Sci 15: 225–229PubMedGoogle Scholar
  84. 84.
    Anagnostou A, Lee ES, Kessimian N, Levinson R, Steiner M (1990) Erythropoietin has a mitogenic and positive chemotactic effect on endothelial cells. Proc Natl Acad Sci USA 87: 5978–5982PubMedCrossRefGoogle Scholar
  85. 85.
    Carlini RG, Reyes AA, Rothstein M (1995) Recombinant human erythropoietin stimulates angiogenesis in vitro. Kidney Int 47: 740–745PubMedGoogle Scholar
  86. 86.
    Yasuda Y, Masuda S, Chikuma M, Inoue K, Nagao M, Sasaki R (1998) Estrogen-dependent production of erythropoietin in uterus and its implication in uterine angiogenesis. J Biol Chem 273: 25381–25387PubMedCrossRefGoogle Scholar
  87. 87.
    Ribatti D, Presta M, Vacca A, Ria R, Giuliani R, Dell’Era P, Nico B, Roncali L, Dammacco F (1999) Human erythropoietin induces a pro-angiogenic phenotype in cultured endothelial cells and stimulates neovascularization in vivo. Blood 93: 2627–2636PubMedGoogle Scholar
  88. 88.
    Yamaji R, Okada T, Moriya M, Naito M, Tsuruo T, Miyatake K, Nakano Y (1996) Brain capillary endothelial cells express two forms of erythropoietin receptor mRNA. Eur J Biochem 239: 494–500PubMedCrossRefGoogle Scholar
  89. 89.
    Martinez-Estrada OM, Rodriguez-Millan E, Gonzalez-De Vicente E, Reina M, Vilaro S, Fabre M (2003) Erythropoietin protects the in vitro blood-brain barrier against VEGF-induced permeability. Eur J Neurosci 18: 2538–2544PubMedCrossRefGoogle Scholar
  90. 90.
    Palmer A, Klein R (2003) Multiple roles of ephrins in morphogenesis, neuronal networking, and brain function. Gene Dev 17: 1429–1450PubMedCrossRefGoogle Scholar
  91. 91.
    Adams RH (2003) Molecular control of arterial-venous blood vessel identity. J Anat 202: 105–112PubMedCrossRefGoogle Scholar
  92. 92.
    Suenobu S, Takakura N, Inada T, Yamada Y, Yuasa H, Zhang XQ, Sakano S, Oike Y, Suda T (2002) A role pf EphB4 receptor and its ligand, ephrin-B2, in erythropoiesis. Biochem Biophys Res Commun 293: 1124–1131PubMedCrossRefGoogle Scholar
  93. 93.
    Yancopoulos GD, Davis S, Gale NW, Rudge JS, Wiegand SJ, Holash J (2000) Vascular-specific growth factors and blood vessel formation. Nature 407: 242–248PubMedCrossRefGoogle Scholar
  94. 94.
    Harik SI, Hritz MA, LaManna JC (1995) Hypoxia-induced brain angiogenesis in the adult rat. J Physiol (London) 485: 525–530Google Scholar
  95. 95.
    Boero JA, Ascher J, Arregui A, Rovainen C, Woolsey TA (1999) Increased brain capillaries in chronic hypoxia. J Appl Physiol 86: 1211–1219PubMedGoogle Scholar
  96. 96.
    LaManna JC, Harik SI (1997) Brain metabolic and vascular adaptations to hypoxia in the rat. Adv Exp Med Biol 428: 163–167PubMedGoogle Scholar
  97. 97.
    uo N-T, Benhayon D, Przybylski RJ, Martin RJ, LaManna JC (1999) Prolonged hypoxia increases vascular endothelial growth factor mRNA and protein in adult mouse brain. J Appl Physiol 86: 260–264Google Scholar
  98. 98.
    Stone J, Itin A, Alon T, Peer J, Gnessin H, Chan-Ling T, Keshet E (1995) Development of retinal vasculature is mediated by hypoxia-induced vascular endothelial growth factor (VEGF) expression by neuroglia. J Neurosci 15: 4738–4747PubMedGoogle Scholar
  99. 99.
    Fine LG, Norman JT (2002) The breathing kidney. J Am Soc Nephrol 13: 1974–1976PubMedCrossRefGoogle Scholar
  100. 100.
    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: 1163–1177PubMedCrossRefGoogle Scholar
  101. 101.
    Carmeliet P (2000) VEGF gene therapy: stimulating angiogenesis or angioma-genesis? Nat Med 6: 1102–1103PubMedCrossRefGoogle Scholar
  102. 102.
    Lee RJ, Springer ML, Blanco-Bose WE, Shaw R, Ursell PC, Blau HM (2000) VEGF gene delivery to myocardium: deleterious effects of unregulated expression. Circulation 102: 898–901PubMedGoogle Scholar
  103. 103.
    Vogel J, Gehrig M, Kuschinsky W, Marti HH (2004) Massive inborn angiogenesis in the brain scarcely raises cerebral blood flow. J Cereb Blood Flow Metab 24: 849–859PubMedCrossRefGoogle Scholar
  104. 104.
    Dor Y, Camenisch TD, Itin A, Fishman GI, McDonald JA, Carmeliet P, Keshet E (2001) A novel role for VEGF in endocardial cushion formation and its potential contribution to congenital heart defects. Development 128: 1531–1538PubMedGoogle Scholar
  105. 105.
    Dor Y, Djonov V, Abramovitch R, Itin A, Fishman GI, Carmeliet P, Goelman G, Keshet E (2002) Conditional switching of VEGF provides new insights into adult neovascularization and proangiogenic therapy. EMBO J 21: 1939–1947PubMedCrossRefGoogle Scholar
  106. 106.
    Dor Y, Porat R, Keshet E (2001) Vascular endothelial growth factor and vascular adjustments to perturbations in oxygen homeostasis. Am J Physiol 280: C1367–C1374Google Scholar
  107. 107.
    Korff T, Kimmina S, Martiny-Baron G, Augustin HG (2001) Blood vessel maturation in a 3-dimensional spheroidal coculture model: direct contact with smooth muscle cells regulates endothelial cell quiescence and abrogates VEGF responsiveness. FASEB J 15: 447–457PubMedCrossRefGoogle Scholar
  108. 108.
    Haigh JJ, Morelli PI, Gerhardt H, Haigh K, Tsien J, Damert A, Miquerol L, Muhlner U, Klein R, Ferrara N et al. (2003) Cortical and retinal defects caused by dosage-dependent reductions in VEGF-A paracrine signaling. Dev Biol 262: 225–241PubMedCrossRefGoogle Scholar
  109. 109.
    Carmeliet P, Ferreira V, Breier G, Pollefeyt S, Kieckens L, Gertsenstein M, Fahrig M, Vandenhoeck A, Harpal K, Eberhardt C et al. (1996) Abnormal blood vessel development and lethality in embryos lacking a single VEGF allele. Nature 380: 435–439PubMedCrossRefGoogle Scholar
  110. 110.
    Ferrara N, Carver-Moore K, Chen H, Dowd M, Lu L, O’Shea KS, Powell-Braxton L, Hillan KJ, Moore MW (1996) Heterozygous embryonic lethality induced by targeted inactivation of the VEGF gene. Nature 380: 439–442PubMedCrossRefGoogle Scholar
  111. 111.
    Miquerol L, Langille BL, Nagy A (2000) Embryonic development is disrupted by modest increases in vascular endothelial growth factor gene expression. Development 127: 3941–3946PubMedGoogle Scholar
  112. 112.
    Detmar M, Brown LF, Schön MP, Elicker BM, Velasco P, Richard L, Fukumura D, Monsky W, Claffey KP, Jain RK (1998) Increased microvascular density and enhanced leukocyte rolling and adhesion in the skin of VEGF transgenic mice. J Invest Dermatol 111: 1–6PubMedCrossRefGoogle Scholar
  113. 113.
    Thurston G, Suri C, Smith K, McClain J, Sato TN, Yancopoulos GD, McDonald DM (1999) Leakage-resistant blood vessels in mice transgenically overexpressing angiopoietin-1. Science 286: 2511–2514PubMedCrossRefGoogle Scholar
  114. 114.
    Larcher F, Murillas R, Bolontrade M, Conti CJ, Jorcano JL (1998) VEGF/VPF overexpression in skin of transgenic mice induces angiogenesis, vascular hyperpermeability and accelerated tumor development. Oncogene 17: 303–311PubMedCrossRefGoogle Scholar
  115. 115.
    Suri C, McClain J, Thurston G, McDonald DM, Zhou H, Oldmixon EH, Sato TN, Yancopoulos GD (1998) Increased vascularization in mice overexpressing angiopoietin-1. Science 282: 468–471PubMedCrossRefGoogle Scholar
  116. 116.
    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: 683–687PubMedCrossRefGoogle Scholar
  117. 117.
    Elson DA, Thurston G, Huang LE, Ginzinger DG, McDonald DM, Johnson RS, Arbeit JM (2001) Induction of hypervascularity without leakage or inflammation in transgenic mice overexpressing hypoxia-inducible factor-1α. Gene Dev 15: 2520–2532PubMedCrossRefGoogle Scholar

Copyright information

© Birkhäuser Verlag/Switzerland 2005

Authors and Affiliations

  • Hugo H. Marti
    • 1
  1. 1.Institute of Physiology and PathophysiologyUniversity of HeidelbergHeidelbergGermany

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