The Role of Matricellular Proteins in Experimental Subarachnoid Hemorrhage-Induced Early Brain Injury

  • Lei Liu
  • Hidenori SuzukiEmail author
Part of the Springer Series in Translational Stroke Research book series (SSTSR)


Subarachnoid hemorrhage (SAH) is a serious life-threatening type of stroke caused by bleeding into the subarachnoid space surrounding the brain. It elicits a wide range of stress responses in brain tissues and results in brain injury. The term early brain injury (EBI) is a concept to explain pathophysiological changes that occur in brain within 72 h of SAH. Matricellular proteins (MCPs) are a class of nonstructural extracellular matrix proteins that exert diverse functions through binding to cell surface receptors, growth factors, cytokines and other MCPs. Until now, some of MCPs have been investigated in clinical SAH settings and laboratory studies. Here, we review the role of MCPs in post-SAH EBI by focusing on osteopontin, tenascin-C, and periostin.


Subarachnoid hemorrhage Early brain injury Matricellular proteins Osteopontin Tenascin-C Periostin 





Blood-brain barrier




Complement inhibiting component of Ephedra sinica


Cerebrospinal fluid


Early brain injury


Extracellular matrix


Epidermal growth factor receptor


Extracellular signal-regulated kinase


Focal adhesion kinase




Integrin-linked kinase


c-Jun N-terminal kinase


Mitogen-activated protein kinase


Matricellular protein


Mitogen-activated protein kinase phosphatase


Matrix metalloproteinase


Nuclear factor




Platelet-derived growth factor receptor




Phosphatidylinositol 3-kinase




Recombinant osteopontin


Subarachnoid hemorrhage


Short-interfering ribonucleic acid


Smooth muscle actin


Embryonic smooth muscle myosin heavy chain


Toll-like receptor




Tenascin-C knockout


Vascular endothelial growth factor


Vascular endothelial growth factor receptor


Vascular smooth muscle cell


Zona occludens


  1. 1.
    Suarez JI, Tarr RW, Selman WR. Aneurysmal subarachnoid hemorrhage. N Engl J Med. 2006;354(4):387–96.CrossRefPubMedGoogle Scholar
  2. 2.
    Cahill J, Zhang JH. Subarachnoid hemorrhage: is it time for a new direction? Stroke. 2009;40(3 Suppl):S86–7.CrossRefPubMedGoogle Scholar
  3. 3.
    Chiodoni C, Colombo MP, Sangaletti S. Matricellular proteins: from homeostasis to inflammation, cancer, and metastasis. Cancer Metastasis Rev. 2010;29(2):295–307.CrossRefPubMedGoogle Scholar
  4. 4.
    Benarroch EE. Extracellular matrix in the CNS: dynamic structure and clinical correlations. Neurology. 2015;85(16):1417–27.CrossRefPubMedGoogle Scholar
  5. 5.
    Wang KX, Denhardt DT. Osteopontin: role in immune regulation and stress responses. Cytokine Growth Factor Rev. 2008;19(5-6):333–45.CrossRefPubMedGoogle Scholar
  6. 6.
    Acar A, Cevik MU, Arikanoglu A, Evliyaoglu O, Basarili MK, Uzar E, et al. Serum levels of calcification inhibitors in patients with intracerebral hemorrhage. Int J Neurosci. 2012;122(5):227–32.CrossRefPubMedGoogle Scholar
  7. 7.
    Suzuki H, Hasegawa Y, Kanamaru K, Zhang JH. Mechanisms of osteopontin-induced stabilization of blood-brain barrier disruption after subarachnoid hemorrhage in rats. Stroke. 2010;41(8):1783–90.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Ferrara N, Gerber HP, LeCouter J. The biology of VEGF and its receptors. Nat Med. 2003;9(6):669–76.CrossRefPubMedGoogle Scholar
  9. 9.
    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(8):916–25.CrossRefPubMedGoogle Scholar
  10. 10.
    Gavard J, Patel V, Gutkind JS. Angiopoietin-1 prevents VEGF-induced endothelial permeability by sequestering Src through mDia. Dev Cell. 2008;14(1):25–36.CrossRefPubMedGoogle Scholar
  11. 11.
    Zuo S, Li W, Li Q, Zhao H, Tang J, Chen Q, et al. Protective effects of Ephedra sinica extract on blood-brain barrier integrity and neurological function correlate with complement C3 reduction after subarachnoid hemorrhage in rats. Neurosci Lett. 2015;609:216–22.CrossRefPubMedGoogle Scholar
  12. 12.
    Enkhjargal B, McBride DW, Manaenko A, Reis C, Sakai Y, Tang J, et al. Intranasal administration of vitamin D attenuates blood-brain barrier disruption through endogenous upregulation of osteopontin and activation of CD44/P-gp glycosylation signaling after subarachnoid hemorrhage in rats. J Cereb Blood Flow Metab. 2016;1:271678X16671147.Google Scholar
  13. 13.
    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(2):612–8.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Sehba FA, Mostafa G, Knopman J, Friedrich V Jr, Bederson JB. Acute alterations in microvascular basal lamina after subarachnoid hemorrhage. J Neurosurg. 2004;101(4):633–40.CrossRefPubMedGoogle Scholar
  15. 15.
    Guo Z, Sun X, He Z, Jiang Y, Zhang X, Zhang JH. Matrix metalloproteinase-9 potentiates early brain injury after subarachnoid hemorrhage. Neurol Res. 2010;32(7):715–20.CrossRefPubMedGoogle Scholar
  16. 16.
    Mahajan SD, Aalinkeel R, Reynolds JL, Nair B, Sykes DE, Bonoiu A, et al. Suppression of MMP-9 expression in brain microvascular endothelial cells (BMVEC) using a gold nanorod (GNR)-siRNA nanoplex. Immunol Investig. 2012;41(4):337–55.CrossRefGoogle Scholar
  17. 17.
    Wu CY, Hsieh HL, Jou MJ, Yang CM. Involvement of p42/p44 MAPK, p38 MAPK, JNK and nuclear factor-kappa B in interleukin-1beta-induced matrix metalloproteinase-9 expression in rat brain astrocytes. J Neurochem. 2004;90(6):1477–88.CrossRefPubMedGoogle Scholar
  18. 18.
    Sozen T, Tsuchiyama R, Hasegawa Y, Suzuki H, Jadhav V, Nishizawa S, et al. Role of interleukin-1beta in early brain injury after subarachnoid hemorrhage in mice. Stroke. 2009;40(7):2519–25.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Naredi S, Lambert G, Friberg P, Zall S, Eden E, Rydenhag B, et al. Sympathetic activation and inflammatory response in patients with subarachnoid haemorrhage. Intensive Care Med. 2006;32(12):1955–61.CrossRefPubMedGoogle Scholar
  20. 20.
    Tan KS, Nackley AG, Satterfield K, Maixner W, Diatchenko L, Flood PM. Beta2 adrenergic receptor activation stimulates pro-inflammatory cytokine production in macrophages via PKA- and NF-kappaB-independent mechanisms. Cell Signal. 2007;19(2):251–60.CrossRefPubMedGoogle Scholar
  21. 21.
    Topkoru BC, Altay O, Duris K, Krafft PR, Yan J, Zhang JH. Nasal administration of recombinant osteopontin attenuates early brain injury after subarachnoid hemorrhage. Stroke. 2013;44(11):3189–94.CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    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(12):711–6.CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Zhang JH. Vascular neural network in subarachnoid hemorrhage. Transl Stroke Res. 2014;5(4):423–8.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Edvinsson LI, Povlsen GK. Vascular plasticity in cerebrovascular disorders. J Cereb Blood Flow Metab. 2011;31(7):1554–71.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Rensen SS, Doevendans PA, van Eys GJ. Regulation and characteristics of vascular smooth muscle cell phenotypic diversity. Neth Heart J. 2007;15(3):100–8.CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Wu J, Zhang Y, Yang P, Enkhjargal B, Manaenko A, Tang J, et al. Recombinant osteopontin stabilizes smooth muscle cell phenotype via integrin receptor/integrin-linked kinase/Rac-1 pathway after subarachnoid hemorrhage in rats. Stroke. 2016;47(5):1319–27.CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Shimamura N, Ohkuma H. Phenotypic transformation of smooth muscle in vasospasm after aneurysmal subarachnoid hemorrhage. Transl Stroke Res. 2014;5(3):357–64.CrossRefPubMedGoogle Scholar
  28. 28.
    Tucker RP, Chiquet-Ehrismann R. The regulation of tenascin expression by tissue microenvironments. Biochim Biophys Acta. 2009;1793(5):888–92.CrossRefPubMedGoogle Scholar
  29. 29.
    Udalova IA, Ruhmann M, Thomson SJ, Midwood KS. Expression and immune function of tenascin-C. Crit Rev Immunol. 2011;31(2):115–45.CrossRefPubMedGoogle Scholar
  30. 30.
    Suzuki H, Kinoshita N, Imanaka-Yoshida K, Yoshida T, Taki W. Cerebrospinal fluid tenascin-C increases preceding the development of chronic shunt-dependent hydrocephalus after subarachnoid hemorrhage. Stroke. 2008;39(5):1610–2.CrossRefPubMedGoogle Scholar
  31. 31.
    Suzuki H, Kanamaru K, Shiba M, Fujimoto M, Imanaka-Yoshida K, Yoshida T, et al. Cerebrospinal fluid tenascin-C in cerebral vasospasm after aneurysmal subarachnoid hemorrhage. J Neurosurg Anesthesiol. 2011;23(4):310–7.CrossRefPubMedGoogle Scholar
  32. 32.
    Shiba M, Suzuki H, Fujimoto M, Shimojo N, Imanaka-Yoshida K, Yoshida T, et al. Imatinib mesylate prevents cerebral vasospasm after subarachnoid hemorrhage via inhibiting tenascin-C expression in rats. Neurobiol Dis. 2012;46(1):172–9.CrossRefPubMedGoogle Scholar
  33. 33.
    Shiba M, Fujimoto M, Imanaka-Yoshida K, Yoshida T, Taki W, Suzuki H. Tenascin-C causes neuronal apoptosis after subarachnoid hemorrhage in rats. Transl Stroke Res. 2014;5(2):238–47.CrossRefPubMedGoogle Scholar
  34. 34.
    Fujimoto M, Shiba M, Kawakita F, Liu L, Shimojo N, Imanaka-Yoshida K, et al. Deficiency of tenascin-C and attenuation of blood-brain barrier disruption following experimental subarachnoid hemorrhage in mice. J Neurosurg. 2015;124(6):1693–702.CrossRefPubMedGoogle Scholar
  35. 35.
    Zhan Y, Krafft PR, Lekic T, Ma Q, Souvenir R, Zhang JH, et al. Imatinib preserves blood-brain barrier integrity following experimental subarachnoid hemorrhage in rats. J Neurosci Res. 2015;93(1):94–103.CrossRefPubMedGoogle Scholar
  36. 36.
    Cahill J, Calvert JW, Zhang JH. Mechanisms of early brain injury after subarachnoid hemorrhage. J Cereb Blood Flow Metab. 2006;26(11):1341–53.CrossRefPubMedGoogle Scholar
  37. 37.
    Wallner K, Li C, Shah PK, Wu KJ, Schwartz SM, Sharifi BG. EGF-Like domain of tenascin-C is proapoptotic for cultured smooth muscle cells. Arterioscler Thromb Vasc Biol. 2004;24(8):1416–21.CrossRefPubMedGoogle Scholar
  38. 38.
    Kudo A. Periostin in fibrillogenesis for tissue regeneration: periostin actions inside and outside the cell. Cell Mol Life Sci. 2011;68(19):3201–7.CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Conway SJ, Izuhara K, Kudo Y, Litvin J, Markwald R, Ouyang G, et al. The role of periostin in tissue remodeling across health and disease. Cell Mol Life Sci. 2014;71(7):1279–88.CrossRefPubMedGoogle Scholar
  40. 40.
    Lv S, Liu H, Cui J, Hasegawa T, Hongo H, Feng W, et al. Histochemical examination of cathepsin K, MMP1 and MMP2 in compressed periodontal ligament during orthodontic tooth movement in periostin deficient mice. J Mol Histol. 2014;45(3):303–9.CrossRefPubMedGoogle Scholar
  41. 41.
    Attur M, Yang Q, Shimada K, Tachida Y, Nagase H, Mignatti P, et al. Elevated expression of periostin in human osteoarthritic cartilage and its potential role in matrix degradation via matrix metalloproteinase-13. FASEB J. 2015;29(10):4107–21.CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Liu L, Kawakita F, Fujimoto M, Nakano F, Imanaka-Yoshida K, Yoshida T, et al. Role of periostin in early brain injury after subarachnoid hemorrhage in mice. Stroke. 2017;48(4):1108–11.CrossRefPubMedGoogle Scholar
  43. 43.
    Kii I, Nishiyama T, Li M, Matsumoto K, Saito M, Amizuka N, et al. Incorporation of tenascin-C into the extracellular matrix by periostin underlies an extracellular meshwork architecture. J Biol Chem. 2010;285(3):2028–39.CrossRefPubMedGoogle Scholar
  44. 44.
    Maruhashi T, Kii I, Saito M, Kudo A. Interaction between periostin and BMP-1 promotes proteolytic activation of lysyl oxidase. J Biol Chem. 2010;285(17):13294–303.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  1. 1.Department of NeurosurgeryMie University Graduate School of MedicineTsuJapan
  2. 2.Research Center for Matrix BiologyMie University Graduate School of MedicineTsuJapan

Personalised recommendations