Skip to main content
SpringerLink
Log in

Triggers and mediators of hemorrhagic transformation in cerebral ischemia

  • Published:
Molecular Neurobiology Aims and scope Submit manuscript

Abstract

Intracerebral hemorrhagic transformation is a multifactorial phenomenon in which ischemic brain tissue converts into a hemorrhagic lesion with blood-vessel leakage, extravasation, and further brain injury. It has been estimated that up to 30–40% of all ischemic strokes undergo spontaneous hemorrhagic transformation, and this phenomenon may become even more prevalent with the increasing use of thrombolytic stroke therapy. An emerging conceptual model suggests that the loss of microvascular integrity and disruption of neurovascular homeostasis connects the experimental findings of blood-cell extravasation to brain injury after hemorrhage. In this short article, we examine mechanisms related to reperfusion injury and oxidative stress, leukocyte infiltration, vascular activation, and dysregulated extracellular proteolysis as potential triggers of hemorrhagic transformation. Perturbations in cell-cell and cell-matrix signaling within the hypothesized neurovascular unit may ultimately lead to neuroinflammation and apoptotic-like cell death in the parenchyma. Further investigations into the molecular mediators of hemorrhagic transformation may reveal new therapeutic targets for this clinically complex problem.

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

Access this article

Log in via an institution

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

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Lyden P.D. and Zivin J.A. (1993) Hemorrhagic transformation after cerebral ischemia: mechanisms and incidence. Cerebrovasc. Brain Metab. Rev. 5, 1–16.

    PubMed  CAS  Google Scholar 

  2. Lapchak P.A. (2002) Hemorrhagic transfromation following ischemic stroke: significance, causes, and relationship to therapy and treatment. Curr. Neurol. Neurosci. Rep. 2, 38–43.

    Article  PubMed  Google Scholar 

  3. Passero S., Ciacci G., and Reale F. (2001) Potential triggering factors of intracerebral hemorrhage. Cerebrovasc. Dis. 12, 220–227.

    Article  PubMed  CAS  Google Scholar 

  4. Gebel J.M. and Broderick J.P. (2000) Intracerebral hemorrhage. Neurol. Clin. 18, 419–438.

    Article  PubMed  CAS  Google Scholar 

  5. Andaluz N., Zuccarello M., and Wagner K.R. (2002) Experimental animal models of intracerebral hemorrhage. Neurosurg. Clin. N. Am. 3, 385–393.

    Article  Google Scholar 

  6. Vahedi K. and Bousser M.G. (2002) Thrombolysis in stroke. Curr. Opin. Hematol. 9, 443–447.

    Article  PubMed  Google Scholar 

  7. Report of the Stroke Progress Review Group, NINDS, http://www.ninds.nih.gov/funding/neural_environment/stroke_prg

  8. Lo E.H., Dalkara T., and Moskowitz M.A. (2003) Mechanisms, challenges and opportunities in stroke. Nat. Rev. Neurosci. 4, 399–415.

    Article  PubMed  CAS  Google Scholar 

  9. del Zoppo G.J. and Hallenbeck J.M. (2000) Advances in the vascular pathophysiology of ischemic stroke. Thromb. Res. 98, 73–81.

    Article  PubMed  Google Scholar 

  10. Petty M.A. and Wettstein J.G. (2001) Elements of cerebral microvascular ischemia. Brain Res. 36, 23–34.

    Article  CAS  Google Scholar 

  11. Petty M.A. and Lo E.H. (2002) Junctional complexes of the blood-brain barrier:permeability changes in neuroinflammation. Prog. Neurobiol. 68, 311–323.

    Article  PubMed  CAS  Google Scholar 

  12. Wolburg H. and Lippoldt A. (2002) Tight junctions of the blood-brain barrier:development, composition and regulation. Vascul. Pharmacol. 38, 323–337.

    Article  PubMed  CAS  Google Scholar 

  13. Huber J.D., Egleton R.D., and Davis T.P. (2001) Molecular physiology and pathophysiology of tight junctions in the blood-brain barrier. Trends Neurosci. 24, 719–725.

    Article  PubMed  CAS  Google Scholar 

  14. Mark K.S. and Davis T.P. (2002) Cerebral microvascular changes in permeability and tight junction induced by hypoxia-reoxygenation. Am. J. Physiol. Heart. Circ. Physiol. 282, H1485-H1494.

    PubMed  CAS  Google Scholar 

  15. Yurchenco P.D. and Schittny J.C. (1990) Molecular architecture of basement membranes. FASEB J. 4, 1577–1590.

    PubMed  CAS  Google Scholar 

  16. Abrahamason D.R. (1986) Recent studies on the structure and pathology of basement membranes. J. Pathol. 149, 247–278.

    Google Scholar 

  17. Mohan P.S. and Spiro R.G. (1986) Macromolecular organization of basement membranes. J. Biol. Chem. 261, 4328–4336.

    PubMed  CAS  Google Scholar 

  18. Siflinger-Birnboim A., Delvecchio P.J., Cooper J.A., Blumenstock F.A., Shepard J.M., and Malik A.B. (1987) Molecular sieving characteristics of cultured endothelial monolayer. J. Cell. Physiol. 132, 111–117.

    Article  PubMed  CAS  Google Scholar 

  19. Cserr F.H. and Bungaard M. (1986) The neuronal microenvironment: a comparative view. Ann. NY. Acad. Sci. 481, 1–6.

    Article  PubMed  CAS  Google Scholar 

  20. Fishman R.A. (1975) Brain edema. N. Engl. J. Med. 293, 706–711.

    Article  PubMed  CAS  Google Scholar 

  21. Carr F.J., McBride M.W., Carswell H.V.O., Graham D., Strahorn P., Clark J.S., et al. (2002) Genetic aspects of stroke: human and experimental studies. J. Cereb. Blood Flow Metab. 22, 767–773.

    Article  PubMed  CAS  Google Scholar 

  22. Wagner K.R. and Broderick J.P. (2001) Hemorrhagic stroke: pathophysiological mechanisms and neuroprotective treatments, Lo E.H. and Marwah J. Neuroprotection. Prominent Press, Scottsdale A2, pp. 471–508.

    Google Scholar 

  23. Mayer S.A. (2002) Intracerebral hemorrhage:natural history and rationale of ultra-early hemostatic therapy. Intensive Care Med. 28, S235-S240.

    Article  PubMed  Google Scholar 

  24. Castillo J., Davalos A., Alvarez-Sabin J., Pumar J.M., Leira R., Silva Y., et al. (2002) Molecular signatures of brain injury after intracerebral hemorrhage. Neurology 58, 624–629.

    PubMed  CAS  Google Scholar 

  25. Golding E.M. (2002) Sequelae following traumatic brain injury. The cerebrovascular perspective. Brain Res. Brain Res. Rev. 38, 377–388.

    Article  PubMed  Google Scholar 

  26. Qiu J., Whalen M.J., Lowenstein P., Fiskum G., Fahy B., Darwish R., et al. (2002) Upregulation of the Fas receptor death-inducing signaling complex after traumatic brain injury in mice and humans. J. Neurosci. 22, 3504–3511.

    PubMed  CAS  Google Scholar 

  27. Zhang X., Chen J., Graham S.H., Du L., Kochanek P.M., Draviam R., et al. (2002) Intranuclear localization of apoptosis-inducing factor (AIF) and large scale DNA fragmentation after traumatic brain injury in rats and in neuronal cultures exposed to peroxynitrite. J. Neurochem. 82, 181–191.

    Article  PubMed  CAS  Google Scholar 

  28. Yang G.Y., Betz A.L., Chenevert T.L., Brunberg J.A., and Hoff J.T. (1994) Experimental intracerebral hemorrhage:relationship between brain edema, blood flow, and blood-brain barrier permeability in rats. J. Neurosurg. 81, 93–102.

    PubMed  CAS  Google Scholar 

  29. Rosand J., Eskey C., Chang Y., Gonzalez R.G., Greenberg S.M., and Koroshetz W.J. (2002) Dynamic single-section CT demonstrates reduced cerebral blood flow in acute intracerebral hemorrhage. Cerebrovasc. Dis. 14, 214–220.

    Article  PubMed  Google Scholar 

  30. Zazulia A.R., Diringer M.N., Videen T.O., Adams R.E., Yundt K., Aiyagari V., et al. (2001) Hypoperfusion without ischemia surrounding acute intracerebral hemorrhage. J. Cereb. Blood Flow Metab. 21, 804–810.

    Article  PubMed  CAS  Google Scholar 

  31. Zhang J., Sima B., Johns L.M., and Macdonald R.L. (1996) Time course of changes in arterial relaxation following subarachnoid hemorrhage in dogs. Neurol. Res. 18, 227–232.

    PubMed  CAS  Google Scholar 

  32. Matsumoto K., Lo E.H., Pierce A.R., Halpern E.F., and Newcomb R. (1996) Secondary elevations in extracellular neurotransmitter amino acids in reperfusion phase following focal cerebral ischemia. J. Cereb. Blood Flow Metab. 16, 114–124.

    Article  PubMed  CAS  Google Scholar 

  33. Chen Y. and Swanson R.A. (2003) Astrocytes and brain injury. J. Cereb. Blood Flow Metab. 23, 137–149.

    Article  PubMed  Google Scholar 

  34. Striggow F., Riek M., Breder J., Henrich-Noack P., Reymann K.G., and Reiser G. (2000) The protease thrombin is an endogenous mediator of hippocampal neuroprotection against ischemia at low concentrations but causes degeneration at high concentrations. Proc. Natl. Acad. Sci. USA 97, 2264–2269.

    Article  PubMed  CAS  Google Scholar 

  35. Xi G., Reiser G., and Keep R.F. (2003) The role of thrombin and thrombin receptors in ischemic, hemorrhagic and traumatic brain injury: deleterious or protective? J. Neurochem. 84, 3–9.

    Article  PubMed  CAS  Google Scholar 

  36. Mayne M., Ni W., Yan H.J., Xue M., Johnston J.B., Del Bigio M.R., et al. (2001) Antisense oligodeoxynucleotide inhibition of tumor necrosis factor-alpha expression is neuroprotective after intracerebral hemorrhage. Stroke 32, 240–248.

    PubMed  CAS  Google Scholar 

  37. Lenzlinger P.M., Marx A., Trentz O., Kossmann T., and Morganti-Kossmann M.C. (2002) Prolonged intrathecal release of soluble Fas following severe traumatic brain injury in humans. J. Neuroimmunol. 122, 167–174.

    Article  PubMed  CAS  Google Scholar 

  38. Regan R.F. and Panter S.S. (1993) Neurotoxicity of hemoglobin in cortical cell culture. Neurosci. Lett. 153, 219–222.

    Article  PubMed  CAS  Google Scholar 

  39. Meguro T., Chen B., Lancon J., and Zhang J.H. (2001) Oxyhemoglobin induces caspase-mediated cell death in cerebral endothelial cells. J. Neurochem. 77, 1128–1135.

    Article  PubMed  CAS  Google Scholar 

  40. Glazner G.W., Boland A., Dresse A.E., Brenneman D.E., Gozes I., and Mattson M.P. (1999) Activity-dependent neurotrophic factor peptide (ADNF9) protects neurons against oxidative stress-induced death. J. Neurochem. 73, 2341–2347.

    Article  PubMed  CAS  Google Scholar 

  41. Willmore L.J., and Rubin J.J. (1984) Effects of antiperoxidants on FeCl2-induced lipid peroxidation and focal edema in rat brain. Exp. Neurol. 83, 62–70.

    Article  PubMed  CAS  Google Scholar 

  42. Chan P.H. (1994) Oxygen radicals in focal cerebral ischemia. Brain Pathol. 4, 59–65.

    Article  PubMed  CAS  Google Scholar 

  43. Abe K., Yoshidomi M., and Kogure K. (1989) Arachidonic acid metabolism in ischemic neuronal damage. Ann. NY Acad. Sci. 559, 259–268.

    Article  PubMed  CAS  Google Scholar 

  44. Glaser K.B., Mobillo D., Channg J.Y., and Senko N. (1993) Phospholipase A2 enzymes: regulation and inhibition. Trends Pharmacol. Sci. 14, 92–98.

    Article  PubMed  CAS  Google Scholar 

  45. Asahi M., Ramahonan R., Sumii T., Wang X., Pauw R.J., Weissig V., et al. (2003) Targeted immunoliposomes reseal vascular damage and reduce hemorrhage after thrombolysis in embolic cerebral ischemia. J. Cereb. Blood Flow Metab. (in press).

  46. Bolton S.J., Anthony D.C., and Perry V.H. (1998) Loss of the tight junction proteins occludin and zonula occludens-1 from cerebral vascular endothelium during neutrophil induced blood-brain barrier breakdown in vivo. Neuroscience. 86, 1245–1257.

    Article  PubMed  CAS  Google Scholar 

  47. Kondo T., Kinouchi H., Kawase M., and Yoshimoto T. (1996) Astroglial cells inhibit the increasing permeability of brain endothelial cell monolayer following hypoxia/reoxygenation. Neurosci. Lett. 19, 101–104.

    Article  Google Scholar 

  48. Fischer S., Wobben M., Kleinstuck J., Renz D., and Schaper W. (2000) Effect of astroglial cells on hypoxia-induced permeability in PBMEC cells. Am. J. Physiol. Cell Physiol. 279, C935-C944.

    PubMed  CAS  Google Scholar 

  49. Wei E.P., Christman C.W., Kontos H.A., and Povlishock J.T. (1985) effects of oxygen radicals on cerebral arterioles. Am. J. Physiol. 248, H157-H162.

    PubMed  CAS  Google Scholar 

  50. Zweier J.L., Kuppusamy P., and Lutty G.A. (1988) Measurement of endothelial cell free radical generation: evidence for a central mechanism of free radical injury in postischemic tissue. Proc. Natl. Acad. Sci. USA 85, 4046–4050.

    Article  PubMed  CAS  Google Scholar 

  51. Franko J., Pomfy M., Novakova B., and Bens L. (1999) Stobadine protects against ischemia-reperfusion induced morphological alterations of cerebral microcirculation in dogs. Life Sci. 65, 1963–1967.

    Article  PubMed  CAS  Google Scholar 

  52. Kim G.W., Lewen A., Copin J., Watson B.D., and Chan P.H. (2001) The cytosolic antioxidant, copper/zinc superoxide dismutase, attenuates blood-brain barrier disruption and oxidative cellular injury after photothrombotic cortical ischemia in mice. Neuroscience 105, 1007–1018.

    Article  PubMed  CAS  Google Scholar 

  53. Schmid-Elsaesser R., Zausinger S., Hungerhuber E., Plesnila N., Baethmann A., Reulen H.J., et al. (1997) Superior neuroprotective efficacy of a novel antioxidant (U-101033E) with improved blood-brain barrier permeability in focal cerebral ischemia. Stroke 28, 2018–2024.

    PubMed  CAS  Google Scholar 

  54. Kondo T, Reaume A.G., Huang T-T., Carlson E., Murakami K., Chen S.F., et al. (1997) Reduction of CuZn-superoxide dismutase activity exacerbates neuronal cell injury and edema formation after transient focal cerebral ischemia. J. Neurosci. 17, 4180–4189.

    PubMed  CAS  Google Scholar 

  55. Lapchak P.A., Chapman D.F., and Zivin J.A. (2001) Pharmacological effects of the spin trap agents N-t-butyl-phenylnitrone (PBN) and 2,2,6,6-tetramethylpiperidine-N-oxyl (TEMPO) in a rabbit thromboembolic stroke model: combination studies with the thrombolytic tissue plasminogen activator. Stroke 32, 147–153.

    PubMed  CAS  Google Scholar 

  56. Asahi M., Asahi K., Wang X., and Lo E.H. (2000) Reduction of tissue plasminogen activator-induced hemorrhage and brain injury by free radical spin trapping after embolic focal cerebral ischemia in rats. J. Cereb. Blood Flow Metab. 20, 452–457.

    Article  PubMed  CAS  Google Scholar 

  57. Haddad J.J. (2002) Redox regulation of pro-inflammatory cytokines and IkappaB-alpha/NF kappaB nuclear translocation and activation. Biochem. Biophys. Res. Commun. 296, 847–856.

    Article  PubMed  CAS  Google Scholar 

  58. Inoue N., Takeshita S., Gao D., Ishida T., Kawashima S., Akita H., et al. (2001) Lysophosphatidylcholine increases the secretion of matrix metalloproteinase 2 through the activation of NADH/NADPH oxidase in cultured aortic endothelial cells. Atherosclerosis 155, 45–52.

    Article  PubMed  CAS  Google Scholar 

  59. Giulian D., Woodward J., Young D.G., Krebs J.F., and Lachman L.B. (1988) Interleukin-1 injected into mammalian brain stimulates astrogliosis and neovascularization. J. Neurosci. 8, 2485–2490.

    PubMed  CAS  Google Scholar 

  60. Holmin S. and Matheisen T. (2000) Intracerebral adminstration of interleukin-1 and induction of inflammation, apoptosis and edema. J. Neurosurg. 92, 108–120.

    Article  PubMed  CAS  Google Scholar 

  61. Shafer R.A. and Murphy S. (1997) Activated astrocytes induce nitric oxide synthase-2 in cerebral endothelium via tumor necrosis factor alpha. Glia 370–379.

  62. Fischer S., Clauss M., Wiesnet M., Renz D., Schaper W., and Karliczek G.F. (1999) Hypoxia induces permeability in brain microvessel endothelial cells via VEGF and NO. Am. J. Physiol. 276, C812-C820.

    PubMed  CAS  Google Scholar 

  63. Barone F.C. and Feuerstein G.Z. (1999) Inflammatory mediators and stroke: new opportunities for novel therapeutics. J. Cereb. Blood Flow Metab. 19, 819–834.

    Article  PubMed  CAS  Google Scholar 

  64. Stanimirovic D. and Satoh K. (2000) Inflammatory mediators of cerebral endothelium: a role in ischemic brain inflammation. Brain Pathol. 10, 113–126.

    Article  PubMed  CAS  Google Scholar 

  65. Zhang W. and Stanimirovic D. (2002) Current and future therapeutic strategies to target inflammation in stroke. Current Drug Target—Inflammation & Allergy 1, 151–166.

    Article  CAS  Google Scholar 

  66. Janoff A. and Zeligs J.D. (1968) Vascular injury and lysis of basement membrane in vitro by neutral protease of human leukocyte. Science 161, 702–704.

    Article  PubMed  CAS  Google Scholar 

  67. Weiss S.J., Peppin G., Ortiz X., Ragsdale C., and Test S.T. (1985) Oxidative autoactivation of latent collagenase by human neutrophils. Science 227, 747–749.

    Article  PubMed  CAS  Google Scholar 

  68. Zhang R., Chopp M., Zhang Z., Jiang N., and Power C. (1998) The expression of P-and E-selectins in three models of middle cerebral artery occlusion. Brain Res. 785, 207–214.

    Article  PubMed  CAS  Google Scholar 

  69. Haraldsen G., Kvale D., Lien B., Farstad I.N., and Brandtzaeg P. Cytokine-regulated expression of E-selectin, intercellular adhesion molecule-1 (ICAM-1), and vascular cell adhesion molecule-1 (VCAM-1) in human microvascular endothelial cells. J. Immunol. 156, 2558–2565.

  70. Gen J.G., Bevilacque M.P., Moore K.L., McIntyre T.M., and Prestcott S.M. (1990) Rapid neurophil adhesion to activated endothelium mediated by GMP-140. Nature 343, 757–760.

    Article  Google Scholar 

  71. Wagner D.D. (1993) Weibel-Palade body: The storage granule for von Willebrand factor and P-selectin. Thromb. Haemostasis 70, 105–110.

    CAS  Google Scholar 

  72. Baggiolini M (1998) Chemokines and leukocyte traffic. Nature 392, 565–568.

    Article  PubMed  CAS  Google Scholar 

  73. Che X., Ye W., Panga L., Wu D.C., Yang G.Y. (2001) Monocyte chemoattractant protein-1 expressed in neurons and astrocytes during focal ischemia in mice. Brain Res. 902, 171–177.

    Article  PubMed  CAS  Google Scholar 

  74. Wang X., Li X., Yaish-Ohad S., Sarau H.M., Barone F.C., and Feuerstein G.Z. (1999) Molecular cloning and expression of the rat monocyte chemotactic protein-3 gene: a possible role in stroke. Brain Res. Mol. Brain Res. 71, 304–312.

    Article  PubMed  CAS  Google Scholar 

  75. Bajetto A., Bonavia R., Barbero S., and Schettini G. (2002) Characterization of chemokines and their receptors in the central nervous system: physiopathological implications. J. Neurochem. 82, 1311–1329.

    Article  PubMed  CAS  Google Scholar 

  76. Couraud P.O. (1998) Infiltration of inflammatory cells through brain endothelium. Pathol. Biol. 46, 176–180.

    PubMed  CAS  Google Scholar 

  77. Rosenberg G.A. (2002) Matrix metalloproteinases in neuroinflammation. Glia 39, 279–291.

    Article  PubMed  Google Scholar 

  78. Wong D. and Dorovini-Zis K. (1992) Upregulation of intercellular adhesion molecule-1 (ICAM-1) expression in primary cultures of human brain microvessel endothelial cells by cytokines and lipopolysaccharide. J. Neuroimmunol. 39, 11–21.

    Article  PubMed  CAS  Google Scholar 

  79. Adamson P., Etienne S., Couraud P.O., Calder V., and Greenwood J. (1999) Lymphocyte migration through brain endothelial cell monolayers involves signaling through endothelial ICAM-1 via a rho-dependent pathway. J. Immunol. 162, 2964–2973.

    PubMed  CAS  Google Scholar 

  80. Etienne-Manneville S., Manneville J.B., Adamson P., Wilbourn B., Greenwood J., and Couraud P. O. (2000) ICAM-I-coupled cytoskeletal rearrangements and transendothelial lymphocyte migration involve intracellular calcium signaling in brain endothelial cell lines. J. Immunol. 165, 3375–3383.

    PubMed  CAS  Google Scholar 

  81. Brown R.C. and Davis T.P. (2002) Calcium modulation of adherens and tight junction function: a potential mechanism for BBB disruption after stroke. Stroke 33, 1706–1711.

    Article  PubMed  CAS  Google Scholar 

  82. Allport J.R., Ding H., Collins T., Gerritsen M.E., and Luscinkas F.W. (1997) Endothelial-dependent mechanisms regulate leukocyte transmigrationL a process involving the proteosome and disruption of vascular-endothelial -cadherin complex at endothelial cell-cell junctions. J. Exp. Med. 186, 517–527.

    Article  PubMed  CAS  Google Scholar 

  83. Zhang Z.G., Zhang L., Jiang Q., Zhang R., Davies K., Powers C., et al. (2000) VEGF enhances angiogenesis and promotes blood-brain barrier leakage in the ischemic brain. J. Clin. Investig 106, 829–838.

    PubMed  CAS  Google Scholar 

  84. Zhang Z.G., Zhang L., Tsang W., Soltanian-Zadeh H., Morris D., Zhang R., et al. (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.

    Article  PubMed  CAS  Google Scholar 

  85. Marti H.J., Bernaudin M., Bellail A., Schoch H., Euler M., Petit E., et al. (2000) Hypoxia-induced vascular endothelial growth factor expression precedes neovascularization after cerebral ischemia. Am. J. Pathol. 156, 965–976.

    PubMed  CAS  Google Scholar 

  86. Croll S.D. and Wiegand S.J. (2001) Vascular growth factors in cerebral ischemia. Mol. Neurobiol. 23, 121–135.

    Article  PubMed  CAS  Google Scholar 

  87. van Bruggen N., Thibodeaux H., Palmer J.T., Lee W.P., Fu L., Cairns B., et al. (1999) VEGF antagonism reduces edema formation and tissue damage after ischemia/reperfusion injury in the mouse brain. J. Clin. Investig 104, 1613–1620.

    Article  PubMed  Google Scholar 

  88. Wagner S., Tagaya M., Koziol J.A., Quaranta V., and del Zoppo G.J. (1997) Rapid disruption of an astrocyte interaction with the extracellular matrix mediated by integrin alpha 6 beta 4 during focal cerebral ischemia/reperfusion. Stroke 28, 858–865.

    PubMed  CAS  Google Scholar 

  89. Tagaya M., Haring H.P., Stuiver I., Wagner S., Abumiya T., Lucero J., et al. (2001) Rapid loss of microvascular integrin expression during focal brain ischemia reflects neuron injury. J. Cereb. Blood Flow Metab. 21, 835–846.

    Article  PubMed  CAS  Google Scholar 

  90. Zhang Z.G., Bower L., Zhang R.L., Chen S., Windham J.P., and Chopp M. (1999) Three-dimensional measurement of cerebral microvascular plasma perfusion, glial fibrillary acidic protein and microtubule associated protein-2 immunoreactivity after embolic stroke in rats: a double fluorescent labeled laser-scanning confocal microscopic study. Brain Res. 844, 55–66.

    Article  PubMed  CAS  Google Scholar 

  91. Hamann G.F., Okada Y., Fitridge R., and del Zoppo G.J. (1995) Microvascular basal lamina antigens disappear during cerebral ischemia and reperfusion. Stroke 26, 2120–2126.

    PubMed  CAS  Google Scholar 

  92. Hamann G.F., Liebetrau M., Martens H., Burggraf D., Kloss C.U., Bultemeier G., et al. (2002) Microvascular basal lamina injury after experimental focal cerebral ischemia and reperfusion in the rat. J. Cereb. Blood Flow Metab. 22, 526–533.

    Article  PubMed  Google Scholar 

  93. Hamann G.F., Okada Y., and del Zoppo G.J. (1996) Hemorrhagic transformation and microvascular integrity during focal cerebral ischemia/reperfusion. J. Cereb. Blood Flow Metab. 16, 1373–1378.

    Article  PubMed  CAS  Google Scholar 

  94. del Zoppo G.J., von Kummer R., and Hamann G.F. (1998) Ischaemic damage of brain microvessels: inherent risks for thrombolytic treatment in stroke. J. Neurol. Neurosurg. Psychiatry 65, 1–9.

    PubMed  Google Scholar 

  95. Gasche Y., Copin J-C., Sugawara T., Fujimura K, and Chan P.H. (2001) Matrix metalloproteinase inhibition prevents oxidative stress-associated blood-brain barrier disruption after transient focal cerebral ischemia. J. Cereb. Blood Flow Metab. 21, 1393–1400.

    Article  PubMed  CAS  Google Scholar 

  96. Lo E.H., Wang X., and Cuzner M.L. (2002) Extracellular proteolysis in brain injury and inflammation:role for plasminogen activators and matrix metalloproteinases. J. Neurosci. Res. 69, 1–9.

    Article  PubMed  CAS  Google Scholar 

  97. Armao D., Kornfeld M., Estrada E.Y., Grossetete M., and Rosenberg G.A. (1997) Neutral proteases and disruption of the blood-brain barrier in rat. Brain Res. 767, 259–264.

    Article  PubMed  CAS  Google Scholar 

  98. Asahi M., Wang X., Mori T., Sumii T., Jung J-C., Moskowitz M.A., et al. (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, 7724–7732.

    PubMed  CAS  Google Scholar 

  99. Asahi M., Asahi K., Jung J.C., del Zoppo G.J., Fini M.E., and Lo E.H. (2000) Role for matrix metalloproteinase 9 after focal cerebral ischemia:effects of gene knockout and enzyme inhibition with BB-94. J. Cereb Blood Flow Metab. 20, 1681–1689.

    Article  PubMed  CAS  Google Scholar 

  100. Fujimura M., Gasche Y., Morita-Fujimura Y., Massengale J., Kawase M., and Chan P.H. (1999) Early appearance of activated matrix metalloproteinase 9 and blood-brain barrier disruption in mice after focal cerebral ischemia and reperfusion. Brain Res. 842, 92–100.

    Article  PubMed  CAS  Google Scholar 

  101. Heo J.H., Lucero J., Abumiya T., Koizol J.A., Copeland B.R., and del Zoppo G.J. (1999) Matrix metalloproteinases increase very early during experimental focal cerebral ischemia. J. Cereb. Blood Flow Metab. 19, 624–633.

    Article  PubMed  CAS  Google Scholar 

  102. Mun-Bryce S. and Rosenberg G.A. (1998) Matrix metalloproteinases in cerebro-vascular disease. J. Cereb. Blood Flow Metab. 18, 1163–1172.

    Article  PubMed  CAS  Google Scholar 

  103. Rosenberg G.A., Navratil M., Barone F., and Feuerstein G. (1996) Proteolytic cascade enzymes increase in focal cerebral ischemia in rat. J. Cereb. Blood Flow Metab. 16, 360–366.

    Article  PubMed  CAS  Google Scholar 

  104. Anthony D.C., Miller K.M., Fearn S., Townsend M.J., Opdennaker G., Wells G.M.A., et al. (1998) Matrix metalloproteinase expression in an experimentally induced DTH model of multiple sclerosis in rat CNS. J. Neuroimmunol. 87, 62–72.

    Article  PubMed  CAS  Google Scholar 

  105. Rosenberg G.A., Estrada E.Y., and Dencoff J.E. (1998) Matrix metalloproteinases and TIMPs are associated with blood-brain barrier opening after reperfusion in rat brain. Stroke 29, 2189–2195.

    PubMed  CAS  Google Scholar 

  106. Jiang X., Namura S., and Nagata I. (2001) Matrix metalloproteinase inhibitor KB-R7785 attenuates brain damage resulting from permanent focal cerebral ischemia in mice. Neurosci. Lett. 305, 41–44.

    Article  PubMed  CAS  Google Scholar 

  107. Romanic A.M., White R.F., Arleth A.J., Ohlstein E.H., and Barone F.C. (1998) Matrix metalloproteinase expression increases after cerebral focal ischemia in rats:inhibition of matrix metalloproteinase-9 reduces infarct size. Stroke 29, 1020–1030.

    PubMed  CAS  Google Scholar 

  108. Lapchak P.A., Chapman D.F., and Zivin J.A. (2000) Metalloproteinase inhibition reduces thrombolytic (tissue plasminogen activator)-induced hemorrhage after thromboembolic stroke. Stroke 31, 3034–3040.

    PubMed  CAS  Google Scholar 

  109. Rosenberg G.A., Estrada E.Y., Dencoff J.E., and Stetler-Stevenson W.G. (1995) Tumor necrosis factor-alpha-induced gelatinase B causes delayed opening of blood-brain barrier: an expanded therapeutic window. Brain Res. 703, 151–155.

    Article  PubMed  CAS  Google Scholar 

  110. Lee S. and Lo E.H. (2003) Induction of caspase-mediated cell death by matrix metalloproteinase after hypoxia-reoxygenation in human brain microvascular endothelial cells. Stroke 34, 250 (abstr).

    Article  Google Scholar 

  111. Fini M.E., Cook J.R., Mohan R., and Brinckerhoff C.E. (1998) Regulation of matrix metalloproteinase gene expression, in Matrix Metalloproteinases (Parks W.C. and Mecham R.P.) Academic Press, New York, NY pp. 299–356.

    Google Scholar 

  112. Wang X., Mori T., Jung J-C., Fini M.E., and Lo E.H. (2002) Secretion of matrix metalloproteinase-2 and -9 after mechanical trauma injury in rat cortical cultures and involvement of MAP kinase. J. Neurotrauma 19, 615–625.

    Article  PubMed  Google Scholar 

  113. Morita-Fujimura Y., Fujimura M., Gasche Y., Copin J., and Chan P.H. (1999) Overexpression of copper and zinc superoxide dismutase in transgenic mice prevents the induction and activation of matrix metalloproteinases after cold injury induced brain trauma. J. Cereb. Blood Flow Metab. 20, 130–138.

    Article  Google Scholar 

  114. Ahn M.Y., Zhang Z.G., Tsang W., and Chopp M. (1999) Endogenous plasminogen activator expression after embolic focal cerebral ischemia in mice. Brain Res. 837, 169–176.

    Article  PubMed  CAS  Google Scholar 

  115. Hosomi N., Lucero J., Heo J.H., Koziol J.A., Copeland B.R., and del Zoppo G.J. (2001) Rapid differential endogenous plasminogen activator expression after acute middle cerebral aretry occlusion. Stroke 32, 1341–1348.

    PubMed  CAS  Google Scholar 

  116. Yepes M., Sankvist M., Wong M.K.K., Coleman T.A., Smith E., Cohan S.L., et al. (2000) Neuroserpin reduces cerebral infarct volume and protects neurons from ischemia-induced apoptosis. Blood 96, 569–576.

    PubMed  CAS  Google Scholar 

  117. NINDS rt-PA Stroke Study Group. (1995) Tissue plasminogen activator for acute ischemic stroke. N. Engl. J. Med. 333, 1581–1587.

    Article  Google Scholar 

  118. Larrue V., von Kummer R., del Zoppo G., and Bluhmki E. (1999) Hemorrhagic transformation in acute ischemic stroke:potential contributing factors in the ECASS study. Stroke 28, 957–960.

    Google Scholar 

  119. NINDS rt-PA Stroke Study Group. (1997) Intracerebral hemorrhage after intravenous TPA therapy for ischemic stroke. Stroke 28, 2109–2118.

    Google Scholar 

  120. Sumii T. and Lo E.H. (2002) Involvement of matrix metalloproteinase in thrombolysis-associated hemorrhagic transformation after embolic focal ischemia in rats. Stroke 33, 831–836.

    Article  PubMed  CAS  Google Scholar 

  121. Montaner J., Alvarez-Sabin J., Molina C.A., Angles A., Abilliera S., Arenillas J., et al. (2001) Matrix metalloproteinase expression is related to hemorrhagic transformation after cardioembolic stroke. Stroke 32, 2762–2767.

    PubMed  CAS  Google Scholar 

  122. Maeda M., Furuichi Y., Uetama N., Moriguchi A., Satoh N., Matsuoka N., et al. (2002) A combined treatment with tacrolimus (FK506) and recombinant tissue plasminogen activator for thrombotic focal cerebral ischemia in rats: increased neuroprotective efficacy and extended therapeutic time window. J. Cereb. Blood Flow Metab. 22, 1205–1211.

    Article  PubMed  CAS  Google Scholar 

  123. Pozzi A., Moberg P.E., Miles L.A., Wagner S., Soloway P., and Gardner H.A. (2000) Elevated matrix metalloprotease and angiostatin levels in integrin alpha 1 knockout mice cause reduced tumor vascularization. Proc. Natl. Acad. Sci. USA 97, 2202–2207.

    Article  PubMed  CAS  Google Scholar 

  124. Aoudjit F., Ptoworowski E.F., and St-Pierre Y. (1998) Bi-directional induction of matrix metalloproteinase-9 and tissue inhibitor of metalloproteinase-1 during T lymphoma/endothelial cell contact: implication of ICAM-1. J. Immunol. 160, 2967–2973.

    PubMed  CAS  Google Scholar 

  125. May A.E., Kalsch T., Maasberg S., Herouy Y., Schmidt R., and Gawaz M. (2002) Engagement of glycoprotein IIb/IIa (alpha-IIb/beta-3) on platelets upregulates CD40L and triggers CD40L-dependent matrix degradation by endothelial cells. Circulation 106, 2111–2117.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Neuroprotection Research Laboratory, Departments of Neurology and Radiology, Massachusetts General Hospital, Boston, MA

    Xiaoying Wang & Eng H. Lo

  2. Program in Neuroscience, Harvard Medical School, Boston, MA

    Xiaoying Wang & Eng H. Lo

Authors
  1. Xiaoying Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Eng H. Lo
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Eng H. Lo.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Wang, X., Lo, E.H. Triggers and mediators of hemorrhagic transformation in cerebral ischemia. Mol Neurobiol 28, 229–244 (2003). https://doi.org/10.1385/MN:28:3:229

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1385/MN:28:3:229

Index Entries

Search

Navigation