Loss of Endothelial Laminin α5 Exacerbates Hemorrhagic Brain Injury

  • Jyoti Gautam
  • Jeffrey H. Miner
  • Yao YaoEmail author
Original Article


Endothelial cells make laminin-411 and laminin-511. Although laminin-411 is well studied, the role of laminin-511 remains largely unknown due to the embryonic lethality of lama5−/− mutants. In this study, we generated endothelium-specific lama5 conditional knockout (α5-TKO) mice and investigated the biological functions of endothelial lama5 in blood-brain barrier (BBB) maintenance under homeostatic conditions and the pathogenesis of intracerebral hemorrhage (ICH). First, the BBB integrity of α5-TKO mice was measured under homeostatic conditions. Next, ICH was induced in α5-TKO mice and their littermate controls using the collagenase model. Various parameters, including injury volume, neuronal death, neurological score, brain edema, BBB integrity, inflammatory cell infiltration, and gliosis, were examined at various time points after injury. Under homeostatic conditions, comparable levels of IgG or exogenous tracers were detected in α5-TKO and control mice. Additionally, no differences in tight junction expression, pericyte coverage, and astrocyte polarity were found in these mice. After ICH, α5-TKO mice displayed enlarged injury volume, increased neuronal death, elevated BBB permeability, exacerbated infiltration of inflammatory cells (leukocytes, neutrophils, and mononuclear cells), aggravated gliosis, unchanged brain edema, and worse neurological function, compared to the controls. These findings suggest that endothelial lama5 is dispensable for BBB maintenance under homeostatic conditions but plays a beneficial role in ICH.


Intracerebral hemorrhage Blood-brain barrier Endothelial cells Laminin 



We thank the Yao Lab members for discussions and suggestions.


This study was supported, in part, by the American Heart Association grant 16SDG29320001 (to YY) and NIH R01DK078314 (to JHM).

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflict of interest.

Ethical Approval

All applicable international. National, and/or institutional guidelines for the care and use of animals were followed. This study was approved by the Institutional Animal Care and Use Committee at the University of Georgia. This study does not contain any studies with human participants performed by any of the authors.

Supplementary material

12975_2019_688_MOESM1_ESM.pdf (220 kb)
ESM 1 (PDF 220 kb)


  1. 1.
    Persidsky Y, Ramirez SH, Haorah J, Kanmogne GD. Blood-brain barrier: structural components and function under physiologic and pathologic conditions. J NeuroImmune Pharmacol. 2006;1(3):223–36. Scholar
  2. 2.
    Liebner S, Dijkhuizen RM, Reiss Y, Plate KH, Agalliu D, Constantin G. Functional morphology of the blood-brain barrier in health and disease. Acta Neuropathol. 2018;135(3):311–36. Scholar
  3. 3.
    Zhao Z, Nelson AR, Betsholtz C, Zlokovic BV. Establishment and dysfunction of the blood-brain barrier. Cell. 2015;163(5):1064–78. Scholar
  4. 4.
    Zlokovic BV. The blood-brain barrier in health and chronic neurodegenerative disorders. Neuron. 2008;57(2):178–201. Scholar
  5. 5.
    Zipser BD, Johanson CE, Gonzalez L, Berzin TM, Tavares R, Hulette CM, et al. Microvascular injury and blood-brain barrier leakage in Alzheimer’s disease. Neurobiol Aging. 2007;28(7):977–86. Scholar
  6. 6.
    van Vliet EA, da Costa AS, Redeker S, van Schaik R, Aronica E, Gorter JA. Blood-brain barrier leakage may lead to progression of temporal lobe epilepsy. Brain. 2007;130(Pt 2):521–34. Scholar
  7. 7.
    Marchi N, Angelov L, Masaryk T, Fazio V, Granata T, Hernandez N, et al. Seizure-promoting effect of blood-brain barrier disruption. Epilepsia. 2007;48(4):732–42. Scholar
  8. 8.
    Wardlaw JM, Doubal F, Armitage P, Chappell F, Carpenter T, Munoz Maniega S, et al. Lacunar stroke is associated with diffuse blood-brain barrier dysfunction. Ann Neurol. 2009;65(2):194–202. Scholar
  9. 9.
    Ohashi KL, Tung DK, Wilson J, Zweifach BW, Schmid-Schonbein GW. Transvascular and interstitial migration of neutrophils in rat mesentery. Microcirculation. 1996;3(2):199–210.CrossRefGoogle Scholar
  10. 10.
    Yadav R, Larbi KY, Young RE, Nourshargh S. Migration of leukocytes through the vessel wall and beyond. Thromb Haemost. 2003;90(4):598–606. Scholar
  11. 11.
    Hoshi O, Ushiki T. Neutrophil extravasation in rat mesenteric venules induced by the chemotactic peptide N-formyl-methionyl-luecylphenylalanine (fMLP), with special attention to a barrier function of the vascular basal lamina for neutrophil migration. Arch Histol Cytol. 2004;67(1):107–14.CrossRefGoogle Scholar
  12. 12.
    Bixel MG, Petri B, Khandoga AG, Khandoga A, Wolburg-Buchholz K, Wolburg H, et al. A CD99-related antigen on endothelial cells mediates neutrophil but not lymphocyte extravasation in vivo. Blood. 2007;109(12):5327–36. Scholar
  13. 13.
    Nirwane A, Yao Y. Laminins and their receptors in the CNS. Biol Rev Camb Philos Soc. 2018.
  14. 14.
    Vracko R, Benditt EP. Capillary basal lamina thickening. Its relationship to endothelial cell death and replacement. J Cell Biol. 1970;47(1):281–5.CrossRefGoogle Scholar
  15. 15.
    Kalluri R. Basement membranes: structure, assembly and role in tumour angiogenesis. Nat Rev Cancer. 2003;3(6):422–33. Scholar
  16. 16.
    LeBleu VS, Macdonald B, Kalluri R. Structure and function of basement membranes. Exp Biol Med (Maywood). 2007;232(9):1121–9. Scholar
  17. 17.
    Yao Y. Extracellular matrix in stroke. In: Jiang W, Yu W, Qu Y, Shi Z, Luo B, Zhang JH, editors. Cerebral ischemic reperfusion injuries (CIRI): bench research and clinical implications. Cham: Springer International Publishing; 2018. p. 121–44.CrossRefGoogle Scholar
  18. 18.
    Colognato H, Yurchenco PD. Form and function: the laminin family of heterotrimers. Dev Dyn. 2000;218(2):213–34.<213::AID-DVDY1>3.0.CO;2-R.CrossRefPubMedGoogle Scholar
  19. 19.
    Yao Y. Laminin: loss-of-function studies. Cell Mol Life Sci. 2017;74(6):1095–115. Scholar
  20. 20.
    Jucker M, Tian M, Norton DD, Sherman C, Kusiak JW. Laminin alpha 2 is a component of brain capillary basement membrane: reduced expression in dystrophic dy mice. Neuroscience. 1996;71(4):1153–61.CrossRefGoogle Scholar
  21. 21.
    Menezes MJ, McClenahan FK, Leiton CV, Aranmolate A, Shan X, Colognato H. The extracellular matrix protein laminin alpha2 regulates the maturation and function of the blood-brain barrier. J Neurosci. 2014;34(46):15260–80. Scholar
  22. 22.
    Hannocks MJ, Pizzo ME, Huppert J, Deshpande T, Abbott NJ, Thorne RG, et al. Molecular characterization of perivascular drainage pathways in the murine brain. J Cereb Blood Flow Metab. 2018;38(4):669–86. Scholar
  23. 23.
    Stratman AN, Malotte KM, Mahan RD, Davis MJ, Davis GE. Pericyte recruitment during vasculogenic tube assembly stimulates endothelial basement membrane matrix formation. Blood. 2009;114(24):5091–101. Scholar
  24. 24.
    Gautam J, Zhang X, Yao Y. The role of pericytic laminin in blood brain barrier integrity maintenance. Sci Rep. 2016;6:36450. Scholar
  25. 25.
    Sixt M, Engelhardt B, Pausch F, Hallmann R, Wendler O, Sorokin LM. Endothelial cell laminin isoforms, laminins 8 and 10, play decisive roles in T cell recruitment across the blood-brain barrier in experimental autoimmune encephalomyelitis. J Cell Biol. 2001;153(5):933–46.CrossRefGoogle Scholar
  26. 26.
    Sorokin LM, Pausch F, Frieser M, Kroger S, Ohage E, Deutzmann R. Developmental regulation of the laminin alpha5 chain suggests a role in epithelial and endothelial cell maturation. Dev Biol. 1997;189(2):285–300. Scholar
  27. 27.
    Yao Y, Chen ZL, Norris EH, Strickland S. Astrocytic laminin regulates pericyte differentiation and maintains blood brain barrier integrity. Nat Commun. 2014;5:3413. Scholar
  28. 28.
    Chen ZL, Yao Y, Norris EH, Kruyer A, Jno-Charles O, Akhmerov A, et al. Ablation of astrocytic laminin impairs vascular smooth muscle cell function and leads to hemorrhagic stroke. J Cell Biol. 2013;202(2):381–95. Scholar
  29. 29.
    Thyboll J, Kortesmaa J, Cao R, Soininen R, Wang L, Iivanainen A, et al. Deletion of the laminin alpha4 chain leads to impaired microvessel maturation. Mol Cell Biol. 2002;22(4):1194–202.CrossRefGoogle Scholar
  30. 30.
    Wu C, Ivars F, Anderson P, Hallmann R, Vestweber D, Nilsson P, et al. Endothelial basement membrane laminin α5 selectively inhibits T lymphocyte extravasation into the brain. Nat Med. 2009;15(5):519–27.CrossRefGoogle Scholar
  31. 31.
    Miner JH, Cunningham J, Sanes JR. Roles for laminin in embryogenesis: exencephaly, syndactyly, and placentopathy in mice lacking the laminin alpha5 chain. J Cell Biol. 1998;143(6):1713–23.CrossRefGoogle Scholar
  32. 32.
    Yao Y. Basement membrane and stroke. J Cereb Blood Flow Metab. 2018:In press.Google Scholar
  33. 33.
    Keep RF, Hua Y, Xi G. Intracerebral haemorrhage: mechanisms of injury and therapeutic targets. Lancet Neurol. 2012;11(8):720–31. Scholar
  34. 34.
    Nguyen NM, Kelley DG, Schlueter JA, Meyer MJ, Senior RM, Miner JH. Epithelial laminin alpha5 is necessary for distal epithelial cell maturation, VEGF production, and alveolization in the developing murine lung. Dev Biol. 2005;282(1):111–25. Scholar
  35. 35.
    Yao Y, Tsirka SE. The CCL2-CCR2 system affects the progression and clearance of intracerebral hemorrhage. Glia. 2012;60(6):908–18. Scholar
  36. 36.
    Klahr AC, Dickson CT, Colbourne F. Seizure activity occurs in the collagenase but not the blood infusion model of striatal hemorrhagic stroke in rats. Transl Stroke Res. 2015;6(1):29–38. Scholar
  37. 37.
    Wu G, Xi G, Hua Y, Sagher O. T2* magnetic resonance imaging sequences reflect brain tissue iron deposition following intracerebral hemorrhage. Transl Stroke Res. 2010;1(1):31–4. Scholar
  38. 38.
    Wan S, Cheng Y, Jin H, Guo D, Hua Y, Keep RF, et al. Microglia activation and polarization after intracerebral hemorrhage in mice: the role of protease-activated receptor-1. Transl Stroke Res. 2016;7(6):478–87. Scholar
  39. 39.
    Iniaghe LO, Krafft PR, Klebe DW, Omogbai EKI, Zhang JH, Tang J. Dimethyl fumarate confers neuroprotection by casein kinase 2 phosphorylation of Nrf2 in murine intracerebral hemorrhage. Neurobiol Dis. 2015;82:349–58. Scholar
  40. 40.
    Wang J, Tsirka SE. Tuftsin fragment 1-3 is beneficial when delivered after the induction of intracerebral hemorrhage. Stroke. 2005;36(3):613–8. Scholar
  41. 41.
    Guo F, Hua Y, Wang J, Keep RF, Xi G. Inhibition of carbonic anhydrase reduces brain injury after intracerebral hemorrhage. Transl Stroke Res. 2012;3(1):130–7. Scholar
  42. 42.
    Miner JH, Patton BL, Lentz SI, Gilbert DJ, Snider WD, Jenkins NA, et al. The laminin alpha chains: expression, developmental transitions, and chromosomal locations of alpha1-5, identification of heterotrimeric laminins 8-11, and cloning of a novel alpha3 isoform. J Cell Biol. 1997;137(3):685–701.CrossRefGoogle Scholar
  43. 43.
    Zudaire E, Gambardella L, Kurcz C, Vermeren S. A computational tool for quantitative analysis of vascular networks. PLoS One. 2011;6(11):e27385. Scholar
  44. 44.
    Siqueira M, Francis D, Gisbert D, Gomes FCA, Stipursky J. Radial glia cells control angiogenesis in the developing cerebral cortex through TGF-beta1 signaling. Mol Neurobiol. 2018;55(5):3660–75. Scholar
  45. 45.
    Salehi A, Jullienne A, Baghchechi M, Hamer M, Walsworth M, Donovan V, et al. Up-regulation of Wnt/beta-catenin expression is accompanied with vascular repair after traumatic brain injury. J Cereb Blood Flow Metab. 2018;38(2):274–89. Scholar
  46. 46.
    Manaenko A, Chen H, Kammer J, Zhang JH, Tang J. Comparison Evans Blue injection routes: intravenous versus intraperitoneal, for measurement of blood-brain barrier in a mice hemorrhage model. J Neurosci Methods. 2011;195(2):206–10. Scholar
  47. 47.
    Lu X, Chen-Roetling J, Regan RF. Systemic hemin therapy attenuates blood-brain barrier disruption after intracerebral hemorrhage. Neurobiol Dis. 2014;70:245–51. Scholar
  48. 48.
    Ma Q, Huang B, Khatibi N, Rolland W 2nd, Suzuki H, Zhang JH, et al. PDGFR-alpha inhibition preserves blood-brain barrier after intracerebral hemorrhage. Ann Neurol. 2011;70(6):920–31. Scholar
  49. 49.
    Keep RF, Hua Y, Xi G. Brain water content. A misunderstood measurement? Transl Stroke Res. 2012;3(2):263–5. Scholar
  50. 50.
    Clark W, Gunion-Rinker L, Lessov N, Hazel K. Citicoline treatment for experimental intracerebral hemorrhage in mice. Stroke. 1998;29(10):2136–40.CrossRefGoogle Scholar
  51. 51.
    Wang J, Rogove AD, Tsirka AE, Tsirka SE. Protective role of tuftsin fragment 1-3 in an animal model of intracerebral hemorrhage. Ann Neurol. 2003;54(5):655–64. Scholar
  52. 52.
    Kisanuki YY, Hammer RE, Miyazaki J, Williams SC, Richardson JA, Yanagisawa M. Tie2-Cre transgenic mice: a new model for endothelial cell-lineage analysis in vivo. Dev Biol. 2001;230(2):230–42. Scholar
  53. 53.
    Constien R, Forde A, Liliensiek B, Grone HJ, Nawroth P, Hammerling G, et al. Characterization of a novel EGFP reporter mouse to monitor Cre recombination as demonstrated by a Tie2 Cre mouse line. Genesis. 2001;30(1):36–44.CrossRefGoogle Scholar
  54. 54.
    Tang Y, Harrington A, Yang X, Friesel RE, Liaw L. The contribution of the Tie2+ lineage to primitive and definitive hematopoietic cells. Genesis. 2010;48(9):563–7. Scholar
  55. 55.
    Bazzoni G, Dejana E. Endothelial cell-to-cell junctions: molecular organization and role in vascular homeostasis. Physiol Rev. 2004;84(3):869–901. Scholar
  56. 56.
    Kniesel U, Wolburg H. Tight junctions of the blood-brain barrier. Cell Mol Neurobiol. 2000;20(1):57–76.CrossRefGoogle Scholar
  57. 57.
    Daneman R, Zhou L, Kebede AA, Barres BA. Pericytes are required for blood-brain barrier integrity during embryogenesis. Nature. 2010;468(7323):562–6. Scholar
  58. 58.
    Armulik A, Genove G, Mae M, Nisancioglu MH, Wallgard E, Niaudet C, et al. Pericytes regulate the blood-brain barrier. Nature. 2010;468(7323):557–61. Scholar
  59. 59.
    Bell RD, Winkler EA, Sagare AP, Singh I, LaRue B, Deane R, et al. Pericytes control key neurovascular functions and neuronal phenotype in the adult brain and during brain aging. Neuron. 2010;68(3):409–27. Scholar
  60. 60.
    Bell RD, Winkler EA, Singh I, Sagare AP, Deane R, Wu Z, et al. Apolipoprotein E controls cerebrovascular integrity via cyclophilin A. Nature. 2012;485(7399):512–6. Scholar
  61. 61.
    Bernacki J, Dobrowolska A, Nierwinska K, Malecki A. Physiology and pharmacological role of the blood-brain barrier. Pharmacol Rep. 2008;60(5):600–22.PubMedGoogle Scholar
  62. 62.
    Bian GL, Wei LC, Shi M, Wang YQ, Cao R, Chen LW. Fluoro-Jade C can specifically stain the degenerative neurons in the substantia nigra of the 1-methyl-4-phenyl-1,2,3,6-tetrahydro pyridine-treated C57BL/6 mice. Brain Res. 2007;1150:55–61. Scholar
  63. 63.
    Sukumari-Ramesh S, Alleyne CH Jr, Dhandapani KM. Astrocyte-specific expression of survivin after intracerebral hemorrhage in mice: a possible role in reactive gliosis? J Neurotrauma. 2012;29(18):2798–804. Scholar
  64. 64.
    Wasserman JK, Yang H, Schlichter LC. Glial responses, neuron death and lesion resolution after intracerebral hemorrhage in young vs. aged rats. Eur J Neurosci. 2008;28(7):1316–28. Scholar
  65. 65.
    Ohsawa K, Imai Y, Kanazawa H, Sasaki Y, Kohsaka S. Involvement of Iba1 in membrane ruffling and phagocytosis of macrophages/microglia. J Cell Sci. 2000;113(Pt 17):3073–84.PubMedGoogle Scholar
  66. 66.
    Jeong HK, Ji K, Min K, Joe EH. Brain inflammation and microglia: facts and misconceptions. Exp Neurobiol. 2013;22(2):59–67. Scholar
  67. 67.
    Song J, Zhang X, Buscher K, Wang Y, Wang H, Di Russo J, et al. Endothelial basement membrane laminin 511 contributes to endothelial junctional tightness and thereby inhibits leukocyte transmigration. Cell Rep. 2017;18(5):1256–69.CrossRefGoogle Scholar
  68. 68.
    Song J, Lokmic Z, Lämmermann T, Rolf J, Wu C, Zhang X, et al. Extracellular matrix of secondary lymphoid organs impacts on B-cell fate and survival. Proc Natl Acad Sci. 2013;110(31):E2915–E24.CrossRefGoogle Scholar
  69. 69.
    Wang S, Voisin MB, Larbi KY, Dangerfield J, Scheiermann C, Tran M, et al. Venular basement membranes contain specific matrix protein low expression regions that act as exit points for emigrating neutrophils. J Exp Med. 2006;203(6):1519–32. Scholar
  70. 70.
    Voisin MB, Probstl D, Nourshargh S. Venular basement membranes ubiquitously express matrix protein low-expression regions: characterization in multiple tissues and remodeling during inflammation. Am J Pathol. 2010;176(1):482–95. Scholar
  71. 71.
    Warren KJ, Iwami D, Harris DG, Bromberg JS, Burrell BE. Laminins affect T cell trafficking and allograft fate. J Clin Invest. 2014;124(5):2204–18. Scholar
  72. 72.
    Yanaka K, Camarata PJ, Spellman SR, Skubitz AP, Furcht LT, Low WC. Laminin peptide ameliorates brain injury by inhibiting leukocyte accumulation in a rat model of transient focal cerebral ischemia. J Cereb Blood Flow Metab. 1997;17(6):605–11. Scholar
  73. 73.
    Chen ZL, Strickland S. Neuronal death in the hippocampus is promoted by plasmin-catalyzed degradation of laminin. Cell. 1997;91(7):917–25.CrossRefGoogle Scholar
  74. 74.
    Chen ZL, Indyk JA, Strickland S. The hippocampal laminin matrix is dynamic and critical for neuronal survival. Mol Biol Cell. 2003;14(7):2665–76. Scholar
  75. 75.
    Omar MH, Kerrisk Campbell M, Xiao X, Zhong Q, Brunken WJ, Miner JH, et al. CNS neurons deposit laminin alpha5 to stabilize synapses. Cell Rep. 2017;21(5):1281–92. Scholar
  76. 76.
    Johnson KM, Milner R, Crocker SJ. Extracellular matrix composition determines astrocyte responses to mechanical and inflammatory stimuli. Neurosci Lett. 2015;600:104–9. Scholar
  77. 77.
    Biswas S, Bachay G, Chu J, Hunter DD, Brunken WJ. Laminin-dependent interaction between astrocytes and microglia: a role in retinal angiogenesis. Am J Pathol. 2017;187(9):2112–27. Scholar
  78. 78.
    Tam WY, Au NPB, Ma CHE. The association between laminin and microglial morphology in vitro. Sci Rep. 2016;6:28580.CrossRefGoogle Scholar
  79. 79.
    Yao Y, Tsirka SE. Chemokines and their receptors in intracerebral hemorrhage. Transl Stroke Res. 2012;3(Suppl 1):70–9. Scholar
  80. 80.
    Ropper AH, Zervas NT. Cerebral blood flow after experimental basal ganglia hemorrhage. Ann Neurol. 1982;11(3):266–71. Scholar
  81. 81.
    Deinsberger W, Vogel J, Kuschinsky W, Auer LM, Boker DK. Experimental intracerebral hemorrhage: description of a double injection model in rats. Neurol Res. 1996;18(5):475–7.CrossRefGoogle Scholar
  82. 82.
    Rosenberg GA, Mun-Bryce S, Wesley M, Kornfeld M. Collagenase-induced intracerebral hemorrhage in rats. Stroke. 1990;21(5):801–7.CrossRefGoogle Scholar
  83. 83.
    Krafft PR, Rolland WB, Duris K, Lekic T, Campbell A, Tang J, et al. Modeling intracerebral hemorrhage in mice: injection of autologous blood or bacterial collagenase. J Vis Exp. 2012;67:e4289. Scholar
  84. 84.
    Tang J, Liu J, Zhou C, Alexander JS, Nanda A, Granger DN, et al. Mmp-9 deficiency enhances collagenase-induced intracerebral hemorrhage and brain injury in mutant mice. J Cereb Blood Flow Metab. 2004;24(10):1133–45. Scholar
  85. 85.
    Manaenko A, Chen H, Zhang JH, Tang J. Comparison of different preclinical models of intracerebral hemorrhage. Acta Neurochir Suppl. 2011;111:9–14. Scholar
  86. 86.
    MacLellan CL, Davies LM, Fingas MS, Colbourne F. The influence of hypothermia on outcome after intracerebral hemorrhage in rats. Stroke. 2006;37(5):1266–70. Scholar
  87. 87.
    Brown MS, Kornfeld M, Mun-Bryce S, Sibbitt RR, Rosenberg GA. Comparison of magnetic resonance imaging and histology in collagenase-induced hemorrhage in the rat. J Neuroimaging. 1995;5(1):23–33.CrossRefGoogle Scholar
  88. 88.
    Gazendam J, Houthoff HJ, Huitema S, Go KG. Cerebral edema formation and blood-brain barrier impairment by intraventricular collagenase infusion. In: Go KG, Baethmann A, editors. Recent progress in the study and therapy of brain edema. Boston: Springer US; 1984. p. 159–73.CrossRefGoogle Scholar
  89. 89.
    Rosenberg GA, Estrada E, Kelley RO, Kornfeld M. Bacterial collagenase disrupts extracellular matrix and opens blood-brain barrier in rat. Neurosci Lett. 1993;160(1):117–9.CrossRefGoogle Scholar
  90. 90.
    James ML, Warner DS, Laskowitz DT. Preclinical models of intracerebral hemorrhage: a translational perspective. Neurocrit Care. 2007;9(1):139–52. Scholar
  91. 91.
    MacLellan CL, Silasi G, Auriat AM, Colbourne F. Rodent models of intracerebral hemorrhage. Stroke. 2010;41(10 Suppl):S95–8. Scholar
  92. 92.
    Xue M, Del Bigio MR. Intracerebral injection of autologous whole blood in rats: time course of inflammation and cell death. Neurosci Lett. 2000;283(3):230–2.CrossRefGoogle Scholar
  93. 93.
    MacLellan CL, Auriat AM, McGie SC, Yan RH, Huynh HD, De Butte MF, et al. Gauging recovery after hemorrhagic stroke in rats: implications for cytoprotection studies. J Cereb Blood Flow Metab. 2006;26(8):1031–42. Scholar
  94. 94.
    Gong C, Hoff JT, Keep RF. Acute inflammatory reaction following experimental intracerebral hemorrhage in rat. Brain Res. 2000;871(1):57–65.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of Pharmaceutical and Biomedical SciencesUniversity of GeorgiaAthensUSA
  2. 2.Division of Nephrology, Department of MedicineWashington University School of MedicineSt. LouisUSA

Personalised recommendations