Advertisement

Hypoxia pp 273-291 | Cite as

Hypoxia-inducible factor in brain

  • Frank R. Sharp
  • Marcelle Bergeron
  • Myriam Bernaudin
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 502)

Abstract

HIF-1 is composed of HIF-1α and HIF-1ß protein subunits. HIF-1 is induced by hypoxia and binds to promoter / enhancer elements and stimulates the transcription of hypoxia-inducible target genes. Because HIF-1 activation might promote cell survival in hypoxic tissues, we studied the effect of stroke on the expression of HIF-1α, HIF-1ß and several HIF-1 target genes in adult rat brain. After focal cerebral ischemia, mRNAs encoding HIF-1α, glucose transporter-1 and several glycolytic enzymes including lactate dehydrogenase were up-regulated in the areas around the infarction. HIF and its target genes were induced by 7.5 hours after the onset of ischemia and increased further at 19 and 24 hours. Since hypoxia induces HIF in other tissues, systemic hypoxia (6% O2 for 4.5h) was also shown to increase HIF-la protein expression in the adult rat brain. It is proposed that decreased blood flow to the penumbra decreases the supply of oxygen and that this induces HIF-1 and its target genes. Because HIF-1 activation may promote cell survival in hypoxic tissues, we studied the effect of hypoxic preconditioning on HIF-1 expression in neonatal rat brain. Hypoxic preconditioning (8% O2/3hrs), a treatment known to protect the newborn rat brain against hypoxic-ischemic injury, markedly increased HIF-1α and HIF-HIF-1β expression. We also studied the effect of two other known HIF-1 inducers, cobalt chloride (CoCl2) and desferrioxamine (DFX), on HIF-1 expression and neuroprotection in newborn brain. HIF-1α and HIF-HIF-1β protein levels were markedly increased after i.p. injection of CoCl2 and DFX. Preconditioning with CoCl2 or DFX 24 hours before the stroke decreased infarction by 75% and 56% respectively, compared with vehicle-injected, littermate controls. Thus, HIF-1 activation could contribute to protective brain preconditioning.

Key Words

hypoxia hypoxia-inducible factor ARNT pre-conditioning ischemic tolerance lactate dehydrogenase stroke cerebral ischemia 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Agani FH, Pichiule P, Chavez JC, and LaManna JC. The Role of Mitochondria in the Regulation of Hypoxia-inducible Factor 1 Expression during Hypoxia. J Biol Chem 275: 35863–35867, 2000.PubMedCrossRefGoogle Scholar
  2. 2.
    Aragones J, Jones DR, Martin S, San Juan MA, Alfranca A, Vidal F, Vara A, Merida I, and Landazuri MO. Evidence for the involvement of diacylglycerol kinase in the activation of hypoxia-inducible transcription factor-1 by low oxygen tension. J Biol Chem 276:2001, in press.Google Scholar
  3. 3.
    Badr GA, Zhang JZ, Tang J, Kern TS, and Ismail-Beigi F. Gluti and glut3 expression, but not capillary density, is increased by cobalt chloride in rat cerebrum and retina. Brain Res Mol Brain Res 64:24–33, 1999.PubMedCrossRefGoogle Scholar
  4. 4.
    Bergeron M, Yu AY, Solway KE, Semenza GL, and Sharp FR. Induction of hypoxia- inducible factor-1 (HIF-1) and its target genes following focal ischaemia in rat brain. Eur J Neurosci 11: 4159–4170, 1999.PubMedCrossRefGoogle Scholar
  5. 5.
    Bittar PG, Charnay Y, Pellerin L, Bouras C, and Magistretti PJ. Selective distribution of lactate dehydrogenase isoenzymes in neurons and astrocytes of human brain. J Cereb Blood Flow Metab 16:1079–1089,1996.PubMedCrossRefGoogle Scholar
  6. 6.
    Chandel NS, and Schumacker PT. Cellular oxygen sensing by mitochondria: old questions, new insight. J Appl Physiol 88: 1880–1889,2000.PubMedCrossRefGoogle Scholar
  7. 7.
    Chen J, Graham SH, Zhu RL, and Simon RP. Stress proteins and tolerance to focal cerebral ischemia. J Cereb Blood Flow Metab 16: 566–577, 1996.PubMedCrossRefGoogle Scholar
  8. 8.
    Cobbs CS, Chen J, Greenberg DA, and Graham SH. Vascular endothelial growth factor expression in transient focal cerebral ischemia in the rat. Neurosci Lett 249: 79–82, 1998.PubMedCrossRefGoogle Scholar
  9. 9.
    Drutel G, Kathmann M, Heron A, Gros C, Mace S, Schwartz JC, and Arrang JM. Two splice variants of the hypoxia-inducible factor HIF-1 alpha as potential dimerization partners of ARNT2 in neurons. Eur J Neurosci 12: 3701–3708, 2000.PubMedCrossRefGoogle Scholar
  10. 10.
    Ebert BL, Firth JD, and Ratcliffe PJ. Hypoxia and mitochondrial inhibitors regulate expression of glucose transporter-1 via distinct Cis-acting sequences. J Biol Chem 270: 29083–29089, 1995.PubMedCrossRefGoogle Scholar
  11. 11.
    Ebert BL, Gleadle JM, JF OR, Bartlett SM, Poulton J, and Ratcliffe PJ. Isoenzyme-specific regulation of genes involved in energy metabolism by hypoxia: similarities with the regulation of erythropoietin. Biochem J 313: 809–814, 1996.PubMedGoogle Scholar
  12. 12.
    Ema M, Hirota K, Mimura J, Abe H, Yodoi J, Sogawa K, Poellinger L, and Fujii-Kuriyama Y. Molecular mechanisms of transcription activation by HLF and HIF1 alpha in response to hypoxia: their stabilization and redox signal-induced interaction with CBP/p300. Embo J 18: 1905–1914, 1999.PubMedCrossRefGoogle Scholar
  13. 13.
    Ema M, Taya S, Yokotani N, Sogawa K, Matsuda Y, and Fujii-Kuriyama Y. A novel bHLH-PAS factor with close sequence similarity to hypoxia-inducible factor 1 alpha regulates the VEGF expression and is potentially involved in lung and vascular development. Proc Natl Acad Sci USA 94: 4273–4278, 1997.PubMedCrossRefGoogle Scholar
  14. 14.
    Fandrey J. Hypoxia-inducible gene expression. Respir Physiol 101: 1–10,1995.PubMedCrossRefGoogle Scholar
  15. 15.
    Firth JD, Ebert BL, Pugh CW, and Ratcliffe PJ. Oxygen-regulated control elements in the phosphoglycerate kinase 1 and lactate dehydrogenase A genes: similarities with the erythropoietin 3′ enhancer. Proc Natl Acad Sci USA 91: 6496–6500, 1994.PubMedCrossRefGoogle Scholar
  16. 16.
    Firth JD, Ebert BL, and Ratcliffe PJ. Hypoxic regulation of lactate dehydrogenase A. Interaction between hypoxia-inducible factor 1 and cAMP response elements. J Biol Chem 270: 21021–21027, 1995.PubMedCrossRefGoogle Scholar
  17. 17.
    Flamme I, Frohlich T, von Reutern M, Kappel A, Damert A, and Risau W. HRF, a putative basic helix-loop-helix-PAS-domain transcription factor is closely related to hypoxia-inducible factor-1 alpha and developmentally expressed in blood vessels. Mech Dev 63:51–60, 1997.PubMedCrossRefGoogle Scholar
  18. 18.
    Forsythe JA, Jiang BH, Iyer NV, Agani F, Leung SW, Koos RD, and Semenza GL. Activation of vascular endothelial growth factor gene transcription by hypoxia- inducible factor 1. Mol Cell Biol 16: 4604–4613, 1996.PubMedGoogle Scholar
  19. 19.
    Gidday JM, Fitzgibbons JC, Shah AR, Kraujalis MJ, and Park TS. Reduction in cerebral ischemic injury in the newborn rat by potentiation of endogenous adenosine. Pediatr Res 38:306–311,1995.PubMedCrossRefGoogle Scholar
  20. 20.
    Gidday JM, Fitzgibbons JC, Shah AR, and Park TS. Neuroprotection from ischemic brain injury by hypoxic preconditioning in the neonatal rat. Neurosci Lett 168: 221–224, 1994.PubMedCrossRefGoogle Scholar
  21. 21.
    Gidday JM, Shah AR, Maceren RG, Wang Q, Pelligrino DA, Holtzman DM, and Park TS. Nitric oxide mediates cerebral ischemic tolerance in a neonatal rat model of hypoxic preconditioning. J Cereb Blood Flow Metab 19:331–340, 1999.PubMedCrossRefGoogle Scholar
  22. 22.
    Gothie E, Richard DE, Berra E, Pages G, and Pouyssegur J. Identification of alternative spliced variants of human hypoxia-inducible factor-1 alpha. J Biol Chem 275: 6922–6927, 2000.PubMedCrossRefGoogle Scholar
  23. 23.
    Gradin K, McGuire J, Wenger RH, Kvietikova I, fhitelaw ML, Toftgard R, Tora L, Gassmann M, and Poellinger L. Functional interference between hypoxia and dioxin signal transduction pathways: competition for recruitment of the Arnt transcription factor. Mol Cell Biol 16:5221–5231, 1996.PubMedGoogle Scholar
  24. 24.
    Haddad GG, and Jiang C. O2-sensing mechanisms in excitable cells: role of plasma membrane K+ channels. Annu Rev Physiol 59: 23–42, 1997.PubMedCrossRefGoogle Scholar
  25. 25.
    Heiss WD, Huber M, Fink GR, Herholz K, Pietrzyk U, Wagner R, and Wienhard K. Progressive derangement of periinfarct viable tissue in ischemic stroke. J Cereb Blood Flow Metab 12: 193–203, 1992.PubMedCrossRefGoogle Scholar
  26. 26.
    Hoffman EC, Reyes H, Chu FF, Sander F, Conley LH, Brooks BA, and Hankinson O. Cloning of a factor required for activity of the Ah (dioxin) receptor. Science 252: 954–958, 1991.PubMedCrossRefGoogle Scholar
  27. 27.
    Hogenesch JB, Chan WK, Jackiw VH, Brown RC, Gu YZ, Pray-Grant M, Perdew GH, and Bradfield CA. Characterization of a subset of the basic-helix-loop-helix-PAS superfamily that interacts with components of the dioxin signaling pathway. J Biol Chem 272: 8581–8593, 1997.PubMedCrossRefGoogle Scholar
  28. 28.
    Hossmann KA. Viability thresholds and the penumbra of focal ischemia [see comments]. Ann Neurol 36: 557–565, 1994.PubMedCrossRefGoogle Scholar
  29. 29.
    Huang LE, Gu J, Schau M, and Bunn HF. Regulation of hypoxia-inducible factor 1 alpha is mediated by an O2- dependent degradation domain via the ubiquitin-proteasome pathway. Proc Natl Acad Sci USA 95: 7987–7992, 1998.PubMedCrossRefGoogle Scholar
  30. 30.
    Huang LE, Willmore WG, Gu J, Goldberg MA, and Bunn HF. Inhibition of hypoxia-inducible factor 1 activation by carbon monoxide and nitric oxide. Implications for oxygen sensing and signaling. J Biol Chem 274: 9038–9044, 1999.PubMedCrossRefGoogle Scholar
  31. 31.
    Iyer NV, Kotch LE, Agani F, Leung SW, Laughner E, Wenger RH, Gassmann M, Gearhart JD, Lawler AM, Yu AY, and Semenza GL. Cellular and developmental control of O2 homeostasis by hypoxia- inducible factor 1 alpha. Genes Dev 12: 149–162, 1998.PubMedCrossRefGoogle Scholar
  32. 32.
    Iyer NV, Kotch LE, Agani F, Leung SW, Laughner E, Wenger RH, Gassmann M, Gearhart JD, Lawler AM, Yu AY, and Semenza GL. Cellular and developmental control of O2 homeostasis by hypoxia-inducible factor 1 alpha. Genes Dev 12: 149–162, 1998.PubMedCrossRefGoogle Scholar
  33. 33.
    Jain S, Maltepe E, Lu MM, Simon C, and Bradfield CA. Expression of ARNT, ARNT2, HIF1 alpha, HIF2 alpha and Ah receptor mRNAs in the developing mouse. Mech Dev 73: 117–123,1998.PubMedCrossRefGoogle Scholar
  34. 34.
    Jiang BH, Rue E, Wang GL, Roe R, and Semenza GL. Dimerization, DNA binding, and transactivation properties of hypoxia- inducible factor 1. J Biol Chem 271: 17771–17778, 1996.PubMedCrossRefGoogle Scholar
  35. 35.
    Jiang BH, Semenza GL, Bauer C, and Marti HH. Hypoxia-inducible factor 1 levels vary exponentially over a physiologically relevant range of O2 tension. Am J Physiol 271: C1172–1180, 1996.PubMedGoogle Scholar
  36. 36.
    Jin KL, Mao XO, Nagayama T, Goldsmith PC, and Greenberg DA. Induction of vascular endothelial growth factor and hypoxia-inducible factor-1 alpha by global ischemia in rat brain. Neuroscience 99: 577–585, 2000.PubMedCrossRefGoogle Scholar
  37. 37.
    Kallio PJ, Pongratz I, Gradin K, McGuire J, and Poellinger L. Activation of hypoxia-inducible factor 1 alpha: posttranscriptional regulation and conformational change by recruitment of the Arnt transcription factor. Proc Natl Acad Sci USA 94: 5667–5672, 1997.PubMedCrossRefGoogle Scholar
  38. 38.
    Kallio PJ, Wilson WJ, O’Brien S, Makino Y, and Poellinger L. Regulation of the hypoxia-inducible transcription factor 1 alpha by the ubiquitin-proteasome pathway. J Biol Chem 274:6519–6525,1999.PubMedCrossRefGoogle Scholar
  39. 39.
    Kinouchi H, Sharp FR, Hill MP, Koistinaho J, Sagar SM, and Chan PH. Induction of 70- kDa heat shock protein and hsp70 mRNA following transient focal cerebral ischemia in the rat. J Cereb Blood Flow Metab 13: 105–115, 1993.PubMedCrossRefGoogle Scholar
  40. 40.
    Lennmyr F, Ata KA, Funa K, Olsson Y, and Terent A. Expression of vascular endothelial growth factor (VEGF) and its receptors (Fit-1 and Flk-1) following permanent and transient occlusion of the middle cerebral artery in the rat. J Neuropathol Exp Neurol 57: 874–882, 1998.PubMedCrossRefGoogle Scholar
  41. 41.
    Liu XH, Kirschenbaum A, Yao S, Stearns ME, Holland JF, Claffey K, and Levine AC. Upregulation of vascular endothelial growth factor by cobalt chloride-simulated hypoxia is mediated by persistent induction of cyclooxygenase-2 in a metastatic human prostate cancer cell line. Clin Exp Metastasis 17: 687–694, 1999.PubMedCrossRefGoogle Scholar
  42. 42.
    Maltepe E, Keith B, Arsham AM, Brorson JR, and Simon MC. The role of ARNT2 in tumor angiogenesis and the neural response to hypoxia. Biochem Biophys Res Commun 273:231–238,2000.PubMedCrossRefGoogle Scholar
  43. 43.
    Maltepe E, Schmidt JV, Baunoch D, Bradfield CA, and Simon MC. Abnormal angiogenesis and responses to glucose and oxygen deprivation in mice lacking the protein ARNT. Nature 386: 403–407, 1997.PubMedCrossRefGoogle Scholar
  44. 44.
    Marti HJ, Bernaudin M, Bellail A, Schoch H, Euler M, Petit E, and Risau W. Hypoxia-induced vascular endothelial growth factor expression precedes neovascularization after cerebral ischemia. Am J Pathol 156: 965–976, 2000.PubMedCrossRefGoogle Scholar
  45. 45.
    Munell F, Burke RE, Bandele A, and Gubits RM. Localization of c-fos, c-jun, and hsp70 mRNA expression in brain after neonatal hypoxia-ischemia. Brain Res Dev Brain Res 77: 111–121,1994.PubMedCrossRefGoogle Scholar
  46. 46.
    Ohh M, Park CW, Ivan M, Hoffman MA, Kim TY, Huang LE, Pavletich N, Chau V, and Kaelin WG. Ubiquitination of hypoxia-inducible factor requires direct binding to the beta-domain of the von Hippel-Lindau protein [see comments]. Nat Cell Biol 2: 423–427, 2000.PubMedCrossRefGoogle Scholar
  47. 47.
    Ozaki T, Katsumoto E, Mui K, Furutsuka D, and Yamagami S. Distribution of Fos- and Jun-related proteins and activator protein-1 composite factors in mouse brain induced by neuroleptics. Neuroscience 84: 1187–1196, 1998.PubMedCrossRefGoogle Scholar
  48. 48.
    Peng J, Zhang L, Drysdale L, and Fong GH. The transcription factor EPAS-1/hypoxia- inducible factor 2alpha plays an important role in vascular remodeling. Proc Natl Acad Sci USA 97:8386–8391,2000.PubMedCrossRefGoogle Scholar
  49. 49.
    Perez-Pinzon MA, Lutz PL, Sick TJ, and Rosenthal M. Adenosine, a “retaliatory” metabolite, promotes anoxia tolerance in turtle brain. J Cereb Blood Flow Metab 13: 728–732, 1993.PubMedCrossRefGoogle Scholar
  50. 50.
    Richard DE, Berra E, and Pouyssegur J. Nonhypoxic pathway mediates the induction of hypoxia-inducible factor 1 alpha in vascular smooth muscle cells. J Biol Chem 275: 26765–26771,2000.PubMedGoogle Scholar
  51. 51.
    Ryan HE, Lo J, and Johnson RS. HIF-1 alpha is required for solid tumor formation and embryonic vascularization. Embo J 17:3005–3015, 1998.PubMedCrossRefGoogle Scholar
  52. 52.
    Salceda S, and Caro J. Hypoxia-inducible factor 1 alpha (HIF-1 alpha) protein is rapidly degraded by the ubiquitin-proteasome system under normoxic conditions. Its stabilization by hypoxia depends on redox-induced changes. J Biol Chem 272: 22642–22647, 1997.PubMedCrossRefGoogle Scholar
  53. 53.
    Semenza GL. Perspectives on oxygen sensing. Cell 98: 281–284, 1999.PubMedCrossRefGoogle Scholar
  54. 54.
    Semenza GL. Regulation of mammalian O2 homeostasis by hypoxia-inducible factor 1. Annu Rev Cell Dev Biol 15: 551–578, 1999.PubMedCrossRefGoogle Scholar
  55. 55.
    Semenza GL. Regulation of mammalian O2 homeostasis by hypoxia-inducible factor 1. Annu Rev Cell Dev Biol 15: 551–578, 1999.PubMedCrossRefGoogle Scholar
  56. 56.
    Semenza GL. Surviving ischemia: adaptive responses mediated by hypoxia-inducible factor 1. J Clin Invest 106: 809–812, 2000.PubMedCrossRefGoogle Scholar
  57. 57.
    Semenza GL, Roth PH, Fang HM, and Wang GL. Transcriptional regulation of genes encoding glycolytic enzymes by hypoxia-inducible factor 1. J Biol Chem 269: 23757–23763,1994.PubMedGoogle Scholar
  58. 58.
    Shiraishi K, Sharp FR, and Simon RP. Sequential metabolic changes in rat brain following middle cerebral artery occlusion: a 2-deoxyglucose study. J Cereb Blood Flow Metab 9: 765–773, 1989.PubMedCrossRefGoogle Scholar
  59. 59.
    States BA, Honkaniemi J, Weinstein PR, and Sharp FR. DNA fragmentation and HSP70 protein induction in hippocampus and cortex occurs in separate neurons following permanent middle cerebral artery occlusions. J Cereb Blood Flow Metab 16: 1165–1175, 1996.PubMedCrossRefGoogle Scholar
  60. 60.
    Tanimoto K, Makino Y, Pereira T, and Poellinger L. Mechanism of regulation of the hypoxia-inducible factor-1 alpha by the von hippel-lindau tumor suppressor protein. Embo J 19:4298–4309,2000.PubMedCrossRefGoogle Scholar
  61. 61.
    Thornton RD, Lane P, Borghaei RC, Pease EA, Caro J, and Mochan E. Interleukin 1 induces hypoxia-inducible factor 1 in human gingival and synovial fibroblasts. Biochem J 350 Pt 1: 307–312, 2000.PubMedCrossRefGoogle Scholar
  62. 62.
    Tian H, Hammer RE, Matsumoto AM, Russell DW, and McKnight SL. The hypoxia- responsive transcription factor EPAS1 is essential for catecholamine homeostasis and protection against heart failure during embryonic development. Genes Dev 12: 3320–3324, 1998.PubMedCrossRefGoogle Scholar
  63. 63.
    Urabe T, Hattori N, Nagamatsu S, Sawa H, and Mizuno Y. Expression of glucose transporters in rat brain following transient focal ischemic injury. J Neurochem 67: 265–271, 1996.PubMedCrossRefGoogle Scholar
  64. 64.
    Vannucci SJ, Clark RR, Koehler-Stec E, Li K, Smith CB, Davies P, Maher F, and Simpson IA. Glucose Transporter Expression in Brain: Relationship to Cerebral Glucose Utilization. Dev Neurosci 20:369–379, 1998.PubMedCrossRefGoogle Scholar
  65. 65.
    Wang GL, Jiang BH, Rue EA, and Semenza GL. Hypoxia-inducible factor 1 is a basic- helix-loop-helix-PAS heterodimer regulated by cellular O2 tension. Proc Natl Acad Sci USA 92:5510–5514,1995.PubMedCrossRefGoogle Scholar
  66. 66.
    Wang GL, Jiang BH, and Semenza GL. Effect of altered redox states on expression and DNA-binding activity of hypoxia-inducible factor 1. Biochem Biophys Res Commun 212: 550–556, 1995.PubMedCrossRefGoogle Scholar
  67. 67.
    Wang GL, Jiang BH, and Semenza GL. Effect of protein kinase and phosphatase inhibitors on expression of hypoxia-inducible factor 1. Biochem Biophys Res Commun 216: 669–675, 1995.PubMedCrossRefGoogle Scholar
  68. 68.
    Wang GL, and Semenza GL. Desferrioxamine induces erythropoietin gene expression and hypoxia- inducible factor 1 DNA-binding activity: implications for models of hypoxia signal transduction. Blood 82: 3610–3615, 1993.PubMedGoogle Scholar
  69. 69.
    Wang GL, and Semenza GL. Desferrioxamine induces erythropoietin gene expression and hypoxia-inducible factor 1 DNA-binding activity: implications for models of hypoxia signal transduction. Blood 82: 3610–3615, 1993.PubMedGoogle Scholar
  70. 70.
    Wang GL, and Semenza GL. Purification and characterization of hypoxia-inducible factor 1. J Biol Chem 270: 1230–1237, 1995.PubMedCrossRefGoogle Scholar
  71. 71.
    Weih M, Bergk A, Isaev NK, Ruscher K, Megow D, Riepe M, Meisel A, Victorov IV, Dirnagl U, and Dirnagi UA-ctDUAF. Induction of ischemic tolerance in rat cortical neurons by 3-nitropropionic acid: chemical preconditioning +AFs-published erratum appears in Neurosci Lett 2000 Jan 14+ADs-278(3):194+AF0. Neurosci Lett 272: 207–210, 1999.PubMedCrossRefGoogle Scholar
  72. 72.
    Wenger RH, and Gassmann M. Oxygen(es) and the hypoxia-inducible factor-1. Biol Chem 378: 609–616, 1997.PubMedGoogle Scholar
  73. 73.
    Whalen WJ, Ganfield R, and Nair P. Effects of breathing O 2 or O 2 +CO 2 and of the injection of neurohumors on the PO 2 of cat cerebral cortex. Stroke 1: 194–200, 1970.PubMedCrossRefGoogle Scholar
  74. 74.
    Wiener CM, Booth G, and Semenza GL. In vivo expression of mRNAs encoding hypoxia-inducible factor 1. Biochem Biophys Res Commun 225: 485–488, 1996.PubMedCrossRefGoogle Scholar
  75. 75.
    Wood SM, Wiesener MS, Yeates KM, Okada N, Pugh CW, Maxwell PH, and Ratcliffe PJ. Selection and analysis of a mutant cell line defective in the hypoxia- inducible factor-1 alpha-subunit (HIF-1 alpha). Characterization of hif- 1 alpha-dependent and — independent hypoxia-inducible gene expression. J Biol Chem 273: 8360–8368, 1998.PubMedCrossRefGoogle Scholar
  76. 76.
    Yu AY, Frid MG, Shimoda LA, Wiener CM, Stenmark K, and Semenza GL. Temporal, spatial, and oxygen-regulated expression of hypoxia-inducible factor-1 in the lung. Am J Physiol 275: L818–826, 1998.PubMedGoogle Scholar
  77. 77.
    Yu AY, Shimoda LA, Iyer NV, Huso DL, Sun X, Mc Williams R, Beaty T, Sham JS, Wiener CM, Sylvester JT, and Semenza GL. Impaired physiological responses to chronic hypoxia in mice partially deficient for hypoxia-inducible factor 1 alpha. J Clin Invest 103: 691–696, 1999.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2001

Authors and Affiliations

  • Frank R. Sharp
    • 1
  • Marcelle Bergeron
    • 1
  • Myriam Bernaudin
    • 1
  1. 1.Department of Neurology, and the Neuroscience ProgramUniversity of CincinnatiCincinnatiUSA

Personalised recommendations