Translational Stroke Research

, Volume 5, Issue 2, pp 174–189 | Cite as

Subarachnoid Hemorrhage: a Review of Experimental Studies on the Microcirculation and the Neurovascular Unit

Original Article

Abstract

Increasingly, experimental research in subarachnoid hemorrhage (SAH) has investigated early brain injury and the microcirculation. A number of pathophysiological changes occur in the cerebral microvessels after SAH including altered vasoreactivity, vasoconstriction, inflammation, blood–brain barrier impairment, increased microthrombi, and inversion of neurovascular coupling. This focused review looks at the current state of knowledge regarding the changes that occur in the microcirculation and the neurovascular unit after SAH.

Keywords

Subarachnoid hemorrhage Neurovascular unit Microcirculation Animal model Arteriole Pathophysiology 

Abbreviations

ADP

Adenosine diphosphate

AMPA

α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid

ASA

Acetylsalicylic acid

ATP

Adenosine triphosphate

BBB

Blood–brain barrier

cGMP

Cyclic guanosine monophosphate

DCI

Delayed cerebral ischemia

eNOS

Endothelial nitric oxide synthase

FITC

Fluorescein isothiocyanate

IgG

Immunoglobulin G

IHC

Immunohistochemistry

iNOS

Inducible nitric oxide synthase

JNK

c-Jun N-terminal kinase

MAPK

Mitogen-activated protein kinase

MMP-9

Matrix metalloproteinase-9

NFkB

Nuclear factor-kB

NMDA

N-methyl-d-aspartate

NO

Nitric oxide

PAR-1

Protease-activated receptor-1

PUMA

p53 upregulated modulator of apoptosis

SAH

Subarachnoid hemorrhage

siRNA

Small interfering RNA

TNFα

Tumor necrosis factor alpha

tPA

Tissue plasminogen activator

uPA-T

Urokinase-type plasminogen activator

VDCC

Voltage-dependent calcium channels

Notes

Acknowledgments

MT receives funding from the Vanier Canada Graduate Scholarship, Canadian Institutes of Health Research, Neurosurgery Research and Education Foundation, and the Joint Cerebrovascular Section of the American Association of Neurological Surgeons and the Congress of Neurological Surgeons. RLM receives grant support from the Brain Aneurysm Foundation, Heart and Stroke Foundation of Canada, and is a stockholder of Edge Therapeutics. RLM is Chief Scientific Officer of Edge Therapeutics.

Conflict of Interest

We declare that we have no conflicts of interest.

References

  1. 1.
    Rosengart AJ, Schultheiss KE, Tolentino J, Macdonald RL. Prognostic factors for outcome in patients with aneurysmal subarachnoid hemorrhage. Stroke. 2007;38:2315–21.PubMedCrossRefGoogle Scholar
  2. 2.
    Fujii M, Yan J, Rolland WB, Soejima Y, Caner B, Zhang JH. Early brain injury, an evolving frontier in subarachnoid hemorrhage research. Transl Stroke Res. 2013;4:432–46.PubMedCrossRefGoogle Scholar
  3. 3.
    Macdonald RL. History and definition of delayed cerebral ischemia. Acta Neurochir Suppl. 2013;115:3–7.PubMedGoogle Scholar
  4. 4.
    Ecker A, Riemenschneider PA. Arteriographic demonstration of spasm of the intracranial arteries, with special reference to saccular arterial aneurysms. J Neurosurg. 1951;8:660–7.PubMedCrossRefGoogle Scholar
  5. 5.
    Macdonald RL, Kassell NF, Mayer S, Ruefenacht D, Schmiedek P, Weidauer S, et al. Clazosentan to overcome neurological ischemia and infarction occurring after subarachnoid hemorrhage (CONSCIOUS-1): randomized, double-blind, placebo-controlled phase 2 dose-finding trial. Stroke. 2008;39:3015–21.PubMedCrossRefGoogle Scholar
  6. 6.
    Macdonald RL, Higashida RT, Keller E, Mayer SA, Molyneux A, Raabe A, et al. Clazosentan, an endothelin receptor antagonist, in patients with aneurysmal subarachnoid haemorrhage undergoing surgical clipping: a randomised, double-blind, placebo-controlled phase 3 trial (CONSCIOUS-2). Lancet Neurol. 2011;10:618–25.PubMedCrossRefGoogle Scholar
  7. 7.
    Macdonald RL, Higashida RT, Keller E, Mayer SA, Molyneux A, Raabe A, et al. Randomized trial of clazosentan in patients with aneurysmal subarachnoid hemorrhage undergoing endovascular coiling. Stroke. 2012;43:1463–9.PubMedCrossRefGoogle Scholar
  8. 8.
    Herz DA, Baez S, Shulman K. Pial microcirculation in subarachnoid hemorrhage. Stroke. 1975;6:417–24.PubMedCrossRefGoogle Scholar
  9. 9.
    Kniesel U, Wolburg H. Tight junctions of the blood–brain barrier. Cell Mol Neurobiol. 2000;20:57–76.PubMedCrossRefGoogle Scholar
  10. 10.
    Armulik A, Genove G, Mae M, Nisancioglu MH, Wallgard E, Niaudet C, et al. Pericytes regulate the blood–brain barrier. Nature. 2010;468:557–61.PubMedCrossRefGoogle Scholar
  11. 11.
    Peppiatt CM, Howarth C, Mobbs P, Attwell D. Bidirectional control of CNS capillary diameter by pericytes. Nature. 2006;443:700–4.PubMedCentralPubMedCrossRefGoogle Scholar
  12. 12.
    Fenstermacher J, Gross P, Sposito N, Acuff V, Pettersen S, Gruber K. Structural and functional variations in capillary systems within the brain. Ann N Y Acad Sci. 1988;529:21–30.PubMedCrossRefGoogle Scholar
  13. 13.
    Oldendorf WH, Cornford ME, Brown WJ. The large apparent work capability of the blood–brain barrier: a study of the mitochondrial content of capillary endothelial cells in brain and other tissues of the rat. Ann Neurol. 1977;1:409–17.PubMedCrossRefGoogle Scholar
  14. 14.
    Sedlakova R, Shivers RR, Del Maestro RF. Ultrastructure of the blood–brain barrier in the rabbit. J Submicrosc Cytol Pathol. 1999;31:149–61.PubMedGoogle Scholar
  15. 15.
    Hawkins BT, Davis TP. The blood–brain barrier/neurovascular unit in health and disease. Pharmacol Rev. 2005;57:173–85.PubMedCrossRefGoogle Scholar
  16. 16.
    Grotta JC, et al. (2002) Report of the Stroke Progress Review Group. National Institute of Neurological Disorders and Stroke. [online], http://www.ninds.nih.gov/find_people/groups/stroke_prg/StrokePRGreport-4-23-02.pdf. Accessed 1 Oct 2013.
  17. 17.
    Lecrux C, Hamel E. The neurovascular unit in brain function and disease. Acta Physiol (Oxf). 2011;203:47–59.CrossRefGoogle Scholar
  18. 18.
    Peppiatt C, Attwell D. Neurobiology: feeding the brain. Nature. 2004;431:137–8.PubMedCrossRefGoogle Scholar
  19. 19.
    Zonta M, Angulo MC, Gobbo S, Rosengarten B, Hossmann KA, Pozzan T, et al. Neuron-to-astrocyte signaling is central to the dynamic control of brain microcirculation. Nat Neurosci. 2003;6:43–50.PubMedCrossRefGoogle Scholar
  20. 20.
    Koide M, Bonev AD, Nelson MT, Wellman GC. Inversion of neurovascular coupling by subarachnoid blood depends on large-conductance Ca2+-activated K+ (BK) channels. Proc Natl Acad Sci U S A. 2012;109:E1387–95.PubMedCentralPubMedCrossRefGoogle Scholar
  21. 21.
    Mulligan SJ, MacVicar BA. Calcium transients in astrocyte endfeet cause cerebrovascular constrictions. Nature. 2004;431:195–9.PubMedCrossRefGoogle Scholar
  22. 22.
    Allan S. The neurovascular unit and the key role of astrocytes in the regulation of cerebral blood flow. Cerebrovasc Dis. 2006;21:137–8.PubMedCrossRefGoogle Scholar
  23. 23.
    Stanimirovic DB, Friedman A. Pathophysiology of the neurovascular unit: disease cause or consequence? J Cereb Blood Flow Metab. 2012;32:1207–21.PubMedCentralPubMedCrossRefGoogle Scholar
  24. 24.
    Zhang JH, Badaut J, Tang J, Obenaus A, Hartman R, Pearce WJ. The vascular neural network—a new paradigm in stroke pathophysiology. Nat Rev Neurol. 2012;8:711–6.PubMedCentralPubMedCrossRefGoogle Scholar
  25. 25.
    Sehba FA, Friedrich V. Early micro vascular changes after subarachnoid hemorrhage. Acta Neurochir Suppl. 2011;110:49–55.PubMedGoogle Scholar
  26. 26.
    Rosenblum WI. Pial arteriolar responses in the mouse brain revisited. Stroke. 1976;7:283–7.PubMedCrossRefGoogle Scholar
  27. 27.
    Kusaka G, Ishikawa M, Nanda A, Granger DN, Zhang JH. Signaling pathways for early brain injury after subarachnoid hemorrhage. J Cereb Blood Flow Metab. 2004;24:916–25.PubMedCrossRefGoogle Scholar
  28. 28.
    Cipolla MJ (2009) “The cerebral microcirculation”. In: Granger DN, Granger J, editors. Integrated systems physiology: From molecule to function #2. San Rafael: Morgan & Claypool Life Sciences.Google Scholar
  29. 29.
    Britz GW, Meno JR, Park IS, Abel TJ, Chowdhary A, Nguyen TS, et al. Time-dependent alterations in functional and pharmacological arteriolar reactivity after subarachnoid hemorrhage. Stroke. 2007;38:1329–35.PubMedCrossRefGoogle Scholar
  30. 30.
    Wiernsperger N, Schulz U, Gygax P. Physiological and morphometric analysis of the microcirculation of the cerebral cortex under acute vasospasm. Stroke. 1981;12:624–7.PubMedCrossRefGoogle Scholar
  31. 31.
    Friedrich B, Muller F, Feiler S, Scholler K, Plesnila N. Experimental subarachnoid hemorrhage causes early and long-lasting microarterial constriction and microthrombosis: an in-vivo microscopy study. J Cereb Blood Flow Metab. 2012;32:447–55.PubMedCentralPubMedCrossRefGoogle Scholar
  32. 32.
    Sun BL, Zheng CB, Yang MF, Yuan H, Zhang SM, Wang LX. Dynamic alterations of cerebral pial microcirculation during experimental subarachnoid hemorrhage. Cell Mol Neurobiol. 2009;29:235–41.PubMedCrossRefGoogle Scholar
  33. 33.
    Ishikawa M, Kusaka G, Yamaguchi N, Sekizuka E, Nakadate H, Minamitani H, et al. Platelet and leukocyte adhesion in the microvasculature at the cerebral surface immediately after subarachnoid hemorrhage. Neurosurgery. 2009;64:546–53.PubMedCrossRefGoogle Scholar
  34. 34.
    Kajita Y, Dietrich HH, Dacey Jr RG. Effects of oxyhemoglobin on local and propagated vasodilatory responses induced by adenosine, adenosine diphosphate, and adenosine triphosphate in rat cerebral arterioles. J Neurosurg. 1996;85:908–16.PubMedCrossRefGoogle Scholar
  35. 35.
    Katusic ZS, Milde JH, Cosentino F, Mitrovic BS. Subarachnoid hemorrhage and endothelial L-arginine pathway in small brain stem arteries in dogs. Stroke. 1993;24:392–9.PubMedCrossRefGoogle Scholar
  36. 36.
    Park KW, Metais C, Dai HB, Comunale ME, Sellke FW. Microvascular endothelial dysfunction and its mechanism in a rat model of subarachnoid hemorrhage. Anesth Analg. 2001;92:990–6.PubMedCrossRefGoogle Scholar
  37. 37.
    Park KW, Dai HB, Metais C, Comunale ME, Sellke FW. Isoflurane does not further impair microvascular vasomotion in a rat model of subarachnoid hemorrhage. Can J Anaesth. 2002;49:427–33.PubMedCrossRefGoogle Scholar
  38. 38.
    Park IS, Meno JR, Witt CE, Chowdhary A, Nguyen TS, Winn HR, et al. Impairment of intracerebral arteriole dilation responses after subarachnoid hemorrhage. Laboratory investigation. J Neurosurg. 2009;111:1008–13.PubMedCrossRefGoogle Scholar
  39. 39.
    Vollmer DG, Takayasu M, Dacey Jr RG. An in vitro comparative study of conducting vessels and penetrating arterioles after experimental subarachnoid hemorrhage in the rabbit. J Neurosurg. 1992;77:113–9.PubMedCrossRefGoogle Scholar
  40. 40.
    Nystoriak MA, O’Connor KP, Sonkusare SK, Brayden JE, Nelson MT, Wellman GC. Fundamental increase in pressure-dependent constriction of brain parenchymal arterioles from subarachnoid hemorrhage model rats due to membrane depolarization. Am J Physiol Heart Circ Physiol. 2011;300:H803–12.PubMedCentralPubMedCrossRefGoogle Scholar
  41. 41.
    Koide M, Bonev AD, Nelson MT, Wellman GC. Subarachnoid blood converts neurally evoked vasodilation to vasoconstriction in rat brain cortex. Acta Neurochir Suppl. 2013;115:167–71.PubMedCentralPubMedGoogle Scholar
  42. 42.
    Ohkuma H, Manabe H, Tanaka M, Suzuki S. Impact of cerebral microcirculatory changes on cerebral blood flow during cerebral vasospasm after aneurysmal subarachnoid hemorrhage. Stroke. 2000;31:1621–7.PubMedCrossRefGoogle Scholar
  43. 43.
    del Zoppo GJ, von Kummer R, Hamann GF. Ischaemic damage of brain microvessels: inherent risks for thrombolytic treatment in stroke. J Neurol Neurosurg Psychiatry. 1998;65:1–9.PubMedCrossRefGoogle Scholar
  44. 44.
    Tso MK, Macdonald RL. Acute microvascular changes after subarachnoid hemorrhage and transient global cerebral ischemia. Stroke Res Treat. 2013;2013:425281.PubMedCentralPubMedGoogle Scholar
  45. 45.
    Titova E, Ostrowski RP, Zhang JH, Tang J. Experimental models of subarachnoid hemorrhage for studies of cerebral vasospasm. Neurol Res. 2009;31:568–81.PubMedCrossRefGoogle Scholar
  46. 46.
    Koide M, Wellman GC. SAH-induced suppression of voltage-gated K(+) (K (V)) channel currents in parenchymal arteriolar myocytes involves activation of the HB-EGF/EGFR pathway. Acta Neurochir Suppl. 2013;115:179–84.PubMedCentralPubMedGoogle Scholar
  47. 47.
    Cach R, Smock T, Popejoy S. Blood-borne factors regulating microvascular constriction in the rat hippocampal slice. Brain Res. 1987;414:1–7.PubMedCrossRefGoogle Scholar
  48. 48.
    Zubkov AY, Tibbs RE, Aoki K, Zhang JH. Prevention of vasospasm in penetrating arteries with MAPK inhibitors in dog double-hemorrhage model. Surg Neurol. 2000;54:221–7.PubMedCrossRefGoogle Scholar
  49. 49.
    Ohkuma H, Itoh K, Shibata S, Suzuki S. Morphological changes of intraparenchymal arterioles after experimental subarachnoid hemorrhage in dogs. Neurosurgery. 1997;41:230–5.PubMedCrossRefGoogle Scholar
  50. 50.
    Asano T, Sano K. Pathogenetic role of no-reflow phenomenon in experimental subarachnoid hemorrhage in dogs. J Neurosurg. 1977;46:454–66.PubMedCrossRefGoogle Scholar
  51. 51.
    Ohkuma H, Suzuki S. Histological dissociation between intra- and extraparenchymal portion of perforating small arteries after experimental subarachnoid hemorrhage in dogs. Acta Neuropathol. 1999;98:374–82.PubMedCrossRefGoogle Scholar
  52. 52.
    Ohkuma H, Suzuki S, Ogane K. Phenotypic modulation of smooth muscle cells and vascular remodeling in intraparenchymal small cerebral arteries after canine experimental subarachnoid hemorrhage. Neurosci Lett. 2003;344:193–6.PubMedCrossRefGoogle Scholar
  53. 53.
    Sabri M, Ai J, Lakovic K, D’abbondanza J, Ilodigwe D, Macdonald RL. Mechanisms of microthrombi formation after experimental subarachnoid hemorrhage. Neuroscience. 2012;224:26–37.PubMedCrossRefGoogle Scholar
  54. 54.
    Johshita H, Kassell NF, Sasaki T, Ogawa H. Impaired capillary perfusion and brain edema following experimental subarachnoid hemorrhage: a morphometric study. J Neurosurg. 1990;73:410–7.PubMedCrossRefGoogle Scholar
  55. 55.
    Sehba FA, Friedrich Jr V, Makonnen G, Bederson JB. Acute cerebral vascular injury after subarachnoid hemorrhage and its prevention by administration of a nitric oxide donor. J Neurosurg. 2007;106:321–9.PubMedCrossRefGoogle Scholar
  56. 56.
    Friedrich V, Flores R, Muller A, Sehba FA. Luminal platelet aggregates in functional deficits in parenchymal vessels after subarachnoid hemorrhage. Brain Res. 2010;1354:179–87.PubMedCrossRefGoogle Scholar
  57. 57.
    Uhl E, Lehmberg J, Steiger HJ, Messmer K. Intraoperative detection of early microvasospasm in patients with subarachnoid hemorrhage by using orthogonal polarization spectral imaging. Neurosurgery. 2003;52:1307–15.PubMedCrossRefGoogle Scholar
  58. 58.
    Dorhout Mees SM, Rinkel GJ, Feigin VL, Algra A, van den Bergh WM, Vermeulen M, & van Gijn J (2007) Calcium antagonists for aneurysmal subarachnoid haemorrhage. Cochrane Database Syst Rev. CD000277.Google Scholar
  59. 59.
    Meyer R, Deem S, Yanez ND, Souter M, Lam A, Treggiari MM. Current practices of triple-H prophylaxis and therapy in patients with subarachnoid hemorrhage. Neurocrit Care. 2010;14:24–36.CrossRefGoogle Scholar
  60. 60.
    Ostergaard L, Aamand R, Karabegovic S, Tietze A, Blicher JU, Mikkelsen IK, et al. The role of the microcirculation in delayed cerebral ischemia and chronic degenerative changes after subarachnoid hemorrhage. J Cereb Blood Flow Metab. 2013;33:1825–37.PubMedCentralPubMedCrossRefGoogle Scholar
  61. 61.
    Yemisci M, Gursoy-Ozdemir Y, Vural A, Can A, Topalkara K, Dalkara T. Pericyte contraction induced by oxidative–nitrative stress impairs capillary reflow despite successful opening of an occluded cerebral artery. Nat Med. 2009;15:1031–7.PubMedCrossRefGoogle Scholar
  62. 62.
    Nihei H, Kassell NF, Dougherty DA, Sasaki T. Does vasospasm occur in small pial arteries and arterioles of rabbits? Stroke. 1991;22:1419–25.PubMedCrossRefGoogle Scholar
  63. 63.
    Perkins E, Kimura H, Parent AD, Zhang JH. Evaluation of the microvasculature and cerebral ischemia after experimental subarachnoid hemorrhage in dogs. J Neurosurg. 2002;97:896–904.PubMedCrossRefGoogle Scholar
  64. 64.
    Josko J. Cerebral angiogenesis and expression of VEGF after subarachnoid hemorrhage (SAH) in rats. Brain Res. 2003;981:58–69.PubMedCrossRefGoogle Scholar
  65. 65.
    Zhou N, Xu T, Bai Y, Prativa S, Xu JZ, Li K, et al. Protective effects of urinary trypsin inhibitor on vascular permeability following subarachnoid hemorrhage in a rat model. CNS Neurosci Ther. 2013;19:659–66.PubMedCrossRefGoogle Scholar
  66. 66.
    Ansar S, Edvinsson L. Subtype activation and interaction of protein kinase C and mitogen-activated protein kinase controlling receptor expression in cerebral arteries and microvessels after subarachnoid hemorrhage. Stroke. 2008;39:185–90.PubMedCrossRefGoogle Scholar
  67. 67.
    Friedrich V, Flores R, Muller A, Bi W, Peerschke EI, Sehba FA. Reduction of neutrophil activity decreases early microvascular injury after subarachnoid haemorrhage. J Neuroinflammation. 2011;8:103.PubMedCentralPubMedCrossRefGoogle Scholar
  68. 68.
    Moore KL. Structure and function of P-selectin glycoprotein ligand-1. Leuk Lymphoma. 1998;29:1–15.PubMedCrossRefGoogle Scholar
  69. 69.
    Yatsushige H, Ostrowski RP, Tsubokawa T, Colohan A, Zhang JH. Role of c-Jun N-terminal kinase in early brain injury after subarachnoid hemorrhage. J Neurosci Res. 2007;85:1436–48.PubMedCrossRefGoogle Scholar
  70. 70.
    Erdo F, Erdo SL. Bimoclomol protects against vascular consequences of experimental subarachnoid hemorrhage in rats. Brain Res Bull. 1998;45:163–6.PubMedCrossRefGoogle Scholar
  71. 71.
    Germano A, Costa C, DeFord SM, Angileri FF, Arcadi F, Pike BR, et al. Systemic administration of a calpain inhibitor reduces behavioral deficits and blood–brain barrier permeability changes after experimental subarachnoid hemorrhage in the rat. J Neurotrauma. 2002;19:887–96.PubMedCrossRefGoogle Scholar
  72. 72.
    Germano A, Caffo M, Angileri FF, Arcadi F, Newcomb-Fernandez J, Caruso G, et al. NMDA receptor antagonist felbamate reduces behavioral deficits and blood–brain barrier permeability changes after experimental subarachnoid hemorrhage in the rat. J Neurotrauma. 2007;24:732–44.PubMedCrossRefGoogle Scholar
  73. 73.
    Imperatore C, Germano A, d’Avella D, Tomasello F, Costa G. Effects of the radical scavenger AVS on behavioral and BBB changes after experimental subarachnoid hemorrhage. Life Sci. 2000;66:779–90.PubMedCrossRefGoogle Scholar
  74. 74.
    Suzuki H, Ayer R, Sugawara T, Chen W, Sozen T, Hasegawa Y, et al. Protective effects of recombinant osteopontin on early brain injury after subarachnoid hemorrhage in rats. Crit Care Med. 2010;38:612–8.PubMedCentralPubMedCrossRefGoogle Scholar
  75. 75.
    Yan J, Manaenko A, Chen S, Klebe D, Ma Q, Caner B, et al. Role of SCH79797 in maintaining vascular integrity in rat model of subarachnoid hemorrhage. Stroke. 2013;44:1410–7.PubMedCrossRefGoogle Scholar
  76. 76.
    Doczi T, Joo F, Adam G, Bozoky B, Szerdahelyi P. Blood–brain barrier damage during the acute stage of subarachnoid hemorrhage, as exemplified by a new animal model. Neurosurgery. 1986;18:733–9.PubMedCrossRefGoogle Scholar
  77. 77.
    Doczi T, Joo F, Sonkodi S, Adam G. Increased vulnerability of the blood–brain barrier to experimental subarachnoid hemorrhage in spontaneously hypertensive rats. Stroke. 1986;17:498–501.PubMedCrossRefGoogle Scholar
  78. 78.
    Germano A, d’Avella D, Imperatore C, Caruso G, Tomasello F. Time-course of blood–brain barrier permeability changes after experimental subarachnoid haemorrhage. Acta Neurochir (Wien). 2000;142:575–80.CrossRefGoogle Scholar
  79. 79.
    Wang Z, Zuo G, Shi XY, Zhang J, Fang Q, Chen G. Progesterone administration modulates cortical TLR4/NF-kappaB signaling pathway after subarachnoid hemorrhage in male rats. Mediators Inflamm. 2011;2011:848309.PubMedCentralPubMedCrossRefGoogle Scholar
  80. 80.
    Smith SL, Scherch HM, Hall ED. Protective effects of tirilazad mesylate and metabolite U-89678 against blood–brain barrier damage after subarachnoid hemorrhage and lipid peroxidative neuronal injury. J Neurosurg. 1996;84:229–33.PubMedCrossRefGoogle Scholar
  81. 81.
    Yatsushige H, Calvert JW, Cahill J, Zhang JH. Limited role of inducible nitric oxide synthase in blood–brain barrier function after experimental subarachnoid hemorrhage. J Neurotrauma. 2006;23:1874–82.PubMedCrossRefGoogle Scholar
  82. 82.
    Scholler K, Trinkl A, Klopotowski M, Thal SC, Plesnila N, Trabold R, et al. Characterization of microvascular basal lamina damage and blood–brain barrier dysfunction following subarachnoid hemorrhage in rats. Brain Res. 2007;1142:237–46.PubMedCrossRefGoogle Scholar
  83. 83.
    Yan J, Chen C, Hu Q, Yang X, Lei J, Yang L, et al. The role of p53 in brain edema after 24 h of experimental subarachnoid hemorrhage in a rat model. Exp Neurol. 2008;214:37–46.PubMedCrossRefGoogle Scholar
  84. 84.
    Yan J, Li L, Khatibi NH, Yang L, Wang K, Zhang W, et al. Blood–brain barrier disruption following subarachnoid hemorrhage may be facilitated through PUMA induction of endothelial cell apoptosis from the endoplasmic reticulum. Exp Neurol. 2011;230:240–7.PubMedCrossRefGoogle Scholar
  85. 85.
    Gules I, Satoh M, Nanda A, Zhang JH. Apoptosis, blood–brain barrier, and subarachnoid hemorrhage. Acta Neurochir Suppl. 2003;86:483–7.PubMedGoogle Scholar
  86. 86.
    Friedrich V, Flores R, Muller A, Sehba FA. Escape of intraluminal platelets into brain parenchyma after subarachnoid hemorrhage. Neuroscience. 2010;165:968–75.PubMedCentralPubMedCrossRefGoogle Scholar
  87. 87.
    Sehba FA, Friedrich V. Cerebral microvasculature is an early target of subarachnoid hemorrhage. Acta Neurochir Suppl. 2013;115:199–205.PubMedGoogle Scholar
  88. 88.
    Sehba FA, Mostafa G, Knopman J, Friedrich Jr V, Bederson JB. Acute alterations in microvascular basal lamina after subarachnoid hemorrhage. J Neurosurg. 2004;101:633–40.PubMedCrossRefGoogle Scholar
  89. 89.
    Sehba FA, Flores R, Muller A, Friedrich V, Chen JF, Britz GW, et al. Adenosine A(2A) receptors in early ischemic vascular injury after subarachnoid hemorrhage. Laboratory investigation. J Neurosurg. 2010;113:826–34.PubMedCentralPubMedCrossRefGoogle Scholar
  90. 90.
    Friedrich V, Flores R, Sehba FA. Cell death starts early after subarachnoid hemorrhage. Neurosci Lett. 2012;512:6–11.PubMedCentralPubMedCrossRefGoogle Scholar
  91. 91.
    Prunell GF, Svendgaard NA, Alkass K, Mathiesen T. Delayed cell death related to acute cerebral blood flow changes following subarachnoid hemorrhage in the rat brain. J Neurosurg. 2005;102:1046–54.PubMedCrossRefGoogle Scholar
  92. 92.
    Peterson EW, Cardoso ER. The blood–brain barrier following experimental subarachnoid hemorrhage. Part 1: Response to insult caused by arterial hypertension. J Neurosurg. 1983;58:338–44.PubMedCrossRefGoogle Scholar
  93. 93.
    Park S, Yamaguchi M, Zhou C, Calvert JW, Tang J, Zhang JH. Neurovascular protection reduces early brain injury after subarachnoid hemorrhage. Stroke. 2004;35:2412–7.PubMedCrossRefGoogle Scholar
  94. 94.
    Claassen J, Carhuapoma JR, Kreiter KT, Du EY, Connolly ES, Mayer SA. Global cerebral edema after subarachnoid hemorrhage: frequency, predictors, and impact on outcome. Stroke. 2002;33:1225–32.PubMedCrossRefGoogle Scholar
  95. 95.
    Zhang S, Wang L, Liu M, Wu B. Tirilazad for aneurysmal subarachnoid haemorrhage. Cochrane Database Syst Rev. 2010. CD006778.Google Scholar
  96. 96.
    Stein SC, Browne KD, Chen XH, Smith DH, Graham DI. Thromboembolism and delayed cerebral ischemia after subarachnoid hemorrhage: an autopsy study. Neurosurgery. 2006;59:781–7.PubMedCrossRefGoogle Scholar
  97. 97.
    Sehba FA, Mostafa G, Friedrich Jr V, Bederson JB. Acute microvascular platelet aggregation after subarachnoid hemorrhage. J Neurosurg. 2005;102:1094–100.PubMedCrossRefGoogle Scholar
  98. 98.
    Sabri M, Ai J, Lass E, D’abbondanza J, Macdonald RL. Genetic elimination of eNOS reduces secondary complications of experimental subarachnoid hemorrhage. J Cereb Blood Flow Metab. 2013;33:1008–14.PubMedCrossRefGoogle Scholar
  99. 99.
    Pisapia JM, Xu X, Kelly J, Yeung J, Carrion G, Tong H, et al. Microthrombosis after experimental subarachnoid hemorrhage: time course and effect of red blood cell-bound thrombin-activated pro-urokinase and clazosentan. Exp Neurol. 2012;233:357–63.PubMedCrossRefGoogle Scholar
  100. 100.
    Ramakrishna R, Sekhar LN, Ramanathan D, Temkin N, Hallam D, Ghodke BV, et al. Intraventricular tissue plasminogen activator for the prevention of vasospasm and hydrocephalus after aneurysmal subarachnoid hemorrhage. Neurosurgery. 2010;67:110–7.PubMedCrossRefGoogle Scholar
  101. 101.
    van den Bergh WM, Algra A, Dorhout Mees SM, van Kooten F, Dirven CM, van Gijn J, et al. Randomized controlled trial of acetylsalicylic acid in aneurysmal subarachnoid hemorrhage: the MASH Study. Stroke. 2006;37:2326–30.PubMedCrossRefGoogle Scholar
  102. 102.
    Dreier JP. The role of spreading depression, spreading depolarization and spreading ischemia in neurological disease. Nat Med. 2011;17:439–47.PubMedCrossRefGoogle Scholar
  103. 103.
    Nicoletti C, Offenhauser N, Jorks D, Major S, Dreier JP “Assessment of neurovascular coupling”. In: Chen J, Xu X-M, Xu ZC, Zhang JH, editors. Animal models of acute neurological injuries II: Injuries and mechanistic assessments. Springer Protocols Handbooks. Totowa, NJ: Humana; 2012. Volume I. pp. 353–72Google Scholar

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© Springer Science+Business Media New York 2014

Authors and Affiliations

  1. 1.Division of NeurosurgerySt. Michael’s HospitalTorontoCanada
  2. 2.Institute of Medical ScienceUniversity of TorontoTorontoCanada
  3. 3.Division of Neurosurgery, Labatt Family Centre of Excellence in Brain Injury and Trauma Research, Keenan Research Centre, Li Ka Shing Knowledge InstituteSt. Michael’s HospitalTorontoCanada
  4. 4.Department of SurgeryUniversity of TorontoTorontoCanada

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