Neurochemical Research

, Volume 40, Issue 7, pp 1537–1545 | Cite as

Aspirin Inhibits Degenerative Changes of Aneurysmal Wall in a Rat Model

  • Shengjie Li
  • Dehui Wang
  • Ye Tian
  • Huijie Wei
  • Ziwei Zhou
  • Li Liu
  • Dong Wang
  • Jing-fei Dong
  • Rongcai Jiang
  • Jianning Zhang
Original Paper


Aneurysmal subarachnoid hemorrhage still has a high mortality and morbidity despite notable advances in surgical approaches to cerebral aneurysm (CA). We examined the role of aspirin in vascular inflammation and degeneration. CA was induced in male Sprague–Dawley rats by ligating left common carotid artery and bilateral posterior renal arteries with or without aspirin treatment. The right anterior cerebral artery/olfactory artery (ACA/OA) bifurcations were stripped and assessed morphologically after Verhoeff’s Van Gieson staining. Blood sample was obtained to examine circulating CD34+ CD133+ endothelial progenitor cells (EPCs), platelet aggregation and platelet counts. Macrophages infiltration in aneurysmal wall was evaluated by immunohistochemistry. Expression of matrix metalloproteinase-2 and 9 (MMP-2 and 9), nuclear factor kappa B (NF-κB), macrophage chemoattractant protein-1 (MCP-1) and vascular cell adhesion molecule-1 (VCAM-1) was examined by RT-PCR. 2 months after CA induction, surgically treated rats manifested aneurysmal degeneration in ACA/OA bifurcations. Aspirin-treated rats exhibited a significant decrease in degradation of internal elastic lamina (IEL), medial layer thinning, CA size and macrophages infiltration with reduced expression of MMP-2 and 9 compared with rats in the CA group. RT-PCR demonstrated that the upregulation of NF-κB, MCP-1 and VCAM-1 after CA induction was reversed by aspirin treatment. Aspirin treatment following CA induction increased circulating EPCs to near control levels and reduced platelet aggregation without changing platelet counts. The evidence suggested that aspirin significantly reduced degeneration of aneurysm walls by inhibiting macrophages-mediated chronic inflammation and mobilizing EPCs.


Aspirin Cerebral aneurysm Endothelial progenitor cells Inflammation Platelet 



Cerebral aneurysm


Endothelial progenitor cells


Platelet-rich plasma


Platelet-poor plasma


Mononuclear cells


Anterior cerebral artery/olfactory artery


Internal elastic lamia


Smooth muscle cells


Matrix metalloproteinase-2


Matrix metalloproteinase-9


Nuclear factor kappa B


Macrophage chemoattractant protein-1


Vascular cell adhesion protein-1


One-way analysis of variance


Endothelial cells


Prostaglandin E2


Prostaglandin E receptor 2


Intercellular adhesion molecule


Platelet endothelial cell adhesion molecule


Tumor necrosis factor-α


Reactive oxygen species



The authors acknowledge Weiyun Cui, Fanglian Chen and Lei Zhou for their excellent technical support. This study is supported by the National Natural Science Foundation of China (Grant Nos.: 81100920, 81200907, 81301629 and 81271359), Tianjin Research Program of Application Foundation and Advanced Technology (Grant Nos.: 12JCQNJC6800 and 11JCZDJC18100), Ontario-China Research and Innovation Fund (Grant No.: 2011DFG33430) and Tianjin colleges and universities of science and technology development fund (Grant No.: 2010013).

Conflict of interest

The authors have no conflicts of interest to declare.


  1. 1.
    Macdonald RL, Cusimano MD, Etminan N, Hanggi D, Hasan D, Ilodigwe D, Jaja B, Lantigua H, Le Roux P, Lo B, Louffat-Olivares A, Mayer S, Molyneux A, Quinn A, Schweizer TA, Schenk T, Spears J, Todd M, Torner J, Vergouwen MD, Wong GK, Collaboration S (2013) Subarachnoid Hemorrhage International Trialists data repository (SAHIT). World Neurosurg 79:418–422PubMedCrossRefGoogle Scholar
  2. 2.
    Hosaka K, Hoh BL (2014) Inflammation and cerebral aneurysms. Transl Stroke Res 5:190–198PubMedCrossRefGoogle Scholar
  3. 3.
    Jamous MA, Nagahiro S, Kitazato KT, Tamura T, Aziz HA, Shono M, Satoh K (2007) Endothelial injury and inflammatory response induced by hemodynamic changes preceding intracranial aneurysm formation: experimental study in rats. J Neurosurg 107:405–411PubMedCrossRefGoogle Scholar
  4. 4.
    Hashimoto T, Meng H, Young WL (2006) Intracranial aneurysms: links among inflammation, hemodynamics and vascular remodeling. Neurol Res 28:372–380PubMedCentralPubMedCrossRefGoogle Scholar
  5. 5.
    Deanfield JE, Halcox JP, Rabelink TJ (2007) Endothelial function and dysfunction: testing and clinical relevance. Circulation 115:1285–1295PubMedGoogle Scholar
  6. 6.
    Chyatte D, Bruno G, Desai S, Todor DR (1999) Inflammation and intracranial aneurysms. Neurosurgery 45:1137–1146 discussion 1146–1137 PubMedCrossRefGoogle Scholar
  7. 7.
    Kataoka K, Taneda M, Asai T, Kinoshita A, Ito M, Kuroda R (1999) Structural fragility and inflammatory response of ruptured cerebral aneurysms. A comparative study between ruptured and unruptured cerebral aneurysms. Stroke 30:1396–1401PubMedCrossRefGoogle Scholar
  8. 8.
    Awtry EH, Loscalzo J (2000) Aspirin. Circulation 101:1206–1218PubMedCrossRefGoogle Scholar
  9. 9.
    Hasan DM, Mahaney KB, Brown RD Jr, Meissner I, Piepgras DG, Huston J, Capuano AW, Torner JC (2011) International Study of Unruptured Intracranial Aneurysms Investigators: aspirin as a promising agent for decreasing incidence of cerebral aneurysm rupture. Stroke 42:3156–3162PubMedCentralPubMedCrossRefGoogle Scholar
  10. 10.
    Hasan DM, Chalouhi N, Jabbour P, Dumont AS, Kung DK, Magnotta VA, Young WL, Hashimoto T, Richard Winn H, Heistad D (2013) Evidence that acetylsalicylic acid attenuates inflammation in the walls of human cerebral aneurysms: preliminary results. J Am Heart Assoc 2:e000019PubMedCentralPubMedCrossRefGoogle Scholar
  11. 11.
    Wei H, Mao Q, Liu L, Xu Y, Chen J, Jiang R, Yin L, Fan Y, Chopp M, Dong J, Zhang J (2011) Changes and function of circulating endothelial progenitor cells in patients with cerebral aneurysm. J Neurosci Res 89:1822–1828PubMedCrossRefGoogle Scholar
  12. 12.
    Urbich C, Dimmeler S (2004) Endothelial progenitor cells: characterization and role in vascular biology. Circ Res 95:343–353PubMedCrossRefGoogle Scholar
  13. 13.
    Miller-Kasprzak E, Jagodzinski PP (2007) Endothelial progenitor cells as a new agent contributing to vascular repair. Arch Immunol Ther Exp 55:247–259CrossRefGoogle Scholar
  14. 14.
    Xu Y, Tian Y, Wei HJ, Chen J, Dong JF, Zacharek A, Zhang JN (2011) Erythropoietin increases circulating endothelial progenitor cells and reduces the formation and progression of cerebral aneurysm in rats. Neuroscience 181:292–299PubMedCrossRefGoogle Scholar
  15. 15.
    Hu Z, Zhang F, Yang Z, Zhang J, Zhang D, Yang N, Zhang Y, Cao K (2008) Low-dose aspirin promotes endothelial progenitor cell migration and adhesion and prevents senescence. Cell Biol Int 32:761–768PubMedCrossRefGoogle Scholar
  16. 16.
    Hazama F, Kataoka H, Yamada E, Kayembe K, Hashimoto N, Kojima M, Kim C (1986) Early changes of experimentally induced cerebral aneurysms in rats. Light-microscopic study. Am J Pathol 124:399–404PubMedCentralPubMedGoogle Scholar
  17. 17.
    Lauer A, Schlunk F, Van Cott EM, Steinmetz H, Lo EH, Foerch C (2011) Antiplatelet pretreatment does not increase hematoma volume in experimental intracerebral hemorrhage. J Cereb Blood Flow Metab 31:1736–1742PubMedCentralPubMedCrossRefGoogle Scholar
  18. 18.
    Basselin M, Ramadan E, Chen M, Rapoport SI (2011) Anti-inflammatory effects of chronic aspirin on brain arachidonic acid metabolites. Neurochem Res 36:139–145PubMedCentralPubMedCrossRefGoogle Scholar
  19. 19.
    Peichev M, Naiyer AJ, Pereira D, Zhu Z, Lane WJ, Williams M, Oz MC, Hicklin DJ, Witte L, Moore MA, Rafii S (2000) Expression of VEGFR-2 and AC133 by circulating human CD34(+) cells identifies a population of functional endothelial precursors. Blood 95:952–958PubMedGoogle Scholar
  20. 20.
    Hristov M, Weber C (2004) Endothelial progenitor cells: characterization, pathophysiology, and possible clinical relevance. J Cell Mol Med 8:498–508PubMedCrossRefGoogle Scholar
  21. 21.
    Aoki T, Kataoka H, Ishibashi R, Nozaki K, Hashimoto N (2008) Simvastatin suppresses the progression of experimentally induced cerebral aneurysms in rats. Stroke 39:1276–1285PubMedCrossRefGoogle Scholar
  22. 22.
    Hashimoto N, Handa H, Nagata I, Hazama F (1980) Experimentally induced cerebral aneurysms in rats: Part V. Relation of hemodynamics in the circle of Willis to formation of aneurysms. Surg Neurol 13:41–45PubMedGoogle Scholar
  23. 23.
    Nagata I, Handa H, Hashimoto N, Hazama F (1980) Experimentally induced cerebral aneurysms in rats: Part VI. Hypertension. Surg Neurol 14:477–479PubMedGoogle Scholar
  24. 24.
    Kim C, Cervos-Navarro J, Kikuchi H, Hashimoto N, Hazama F (1992) Alterations in cerebral vessels in experimental animals and their possible relationship to the development of aneurysms. Surg Neurol 38:331–337PubMedCrossRefGoogle Scholar
  25. 25.
    Tamura T, Jamous MA, Kitazato KT, Yagi K, Tada Y, Uno M, Nagahiro S (2009) Endothelial damage due to impaired nitric oxide bioavailability triggers cerebral aneurysm formation in female rats. J Hypertens 27:1284–1292PubMedCrossRefGoogle Scholar
  26. 26.
    Chalouhi N, Ali MS, Jabbour PM, Tjoumakaris SI, Gonzalez LF, Rosenwasser RH, Koch WJ, Dumont AS (2012) Biology of intracranial aneurysms: role of inflammation. J Cereb Blood Flow Metab 32:1659–1676PubMedCentralPubMedCrossRefGoogle Scholar
  27. 27.
    Aoki T, Nishimura M, Matsuoka T, Yamamoto K, Furuyashiki T, Kataoka H, Kitaoka S, Ishibashi R, Ishibazawa A, Miyamoto S, Morishita R, Ando J, Hashimoto N, Nozaki K, Narumiya S (2011) PGE(2)-EP(2) signalling in endothelium is activated by haemodynamic stress and induces cerebral aneurysm through an amplifying loop via NF-kappaB. Br J Pharmacol 163:1237–1249PubMedCentralPubMedCrossRefGoogle Scholar
  28. 28.
    Piatkowski A, Grieb G, Simons D, Bernhagen J, van der Hulst RR (2013) Endothelial progenitor cells–potential new avenues to improve neoangiogenesis and reendothelialization. Int Rev Cell Mol Biol 306:43–81PubMedCrossRefGoogle Scholar
  29. 29.
    Werner N, Kosiol S, Schiegl T, Ahlers P, Walenta K, Link A, Bohm M, Nickenig G (2005) Circulating endothelial progenitor cells and cardiovascular outcomes. N Engl J Med 353:999–1007PubMedCrossRefGoogle Scholar
  30. 30.
    Leone AM, Valgimigli M, Giannico MB, Zaccone V, Perfetti M, D’Amario D, Rebuzzi AG, Crea F (2009) From bone marrow to the arterial wall: the ongoing tale of endothelial progenitor cells. Eur Heart J 30:890–899PubMedCrossRefGoogle Scholar
  31. 31.
    Xu MG, Men LN, Zu Y, Zhao CY, Meng XC, Wang T (2011) The functions of endothelial progenitor cells were significantly improved after treatment with intravenous immunoglobulin and aspirin in children with Kawasaki disease. Pediatr Cardiol 32:455–460PubMedCrossRefGoogle Scholar
  32. 32.
    Aoki T, Kataoka H, Ishibashi R, Nozaki K, Hashimoto N (2008) Nifedipine inhibits the progression of an experimentally induced cerebral aneurysm in rats with associated down-regulation of NF-kappa B transcriptional activity. Curr Neurovasc Res 5:37–45PubMedCrossRefGoogle Scholar
  33. 33.
    Aoki T, Kataoka H, Shimamura M, Nakagami H, Wakayama K, Moriwaki T, Ishibashi R, Nozaki K, Morishita R, Hashimoto N (2007) NF-kappaB is a key mediator of cerebral aneurysm formation. Circulation 116:2830–2840PubMedCrossRefGoogle Scholar
  34. 34.
    Aoki T, Kataoka H, Ishibashi R, Nozaki K, Egashira K, Hashimoto N (2009) Impact of monocyte chemoattractant protein-1 deficiency on cerebral aneurysm formation. Stroke 40:942–951PubMedCrossRefGoogle Scholar
  35. 35.
    Hasan DM, Mahaney KB, Magnotta VA, Kung DK, Lawton MT, Hashimoto T, Winn HR, Saloner D, Martin A, Gahramanov S, Dosa E, Neuwelt E, Young WL (2012) Macrophage imaging within human cerebral aneurysms wall using ferumoxytol-enhanced MRI: a pilot study. Arterioscler Thromb Vasc Biol 32:1032–1038PubMedCentralPubMedCrossRefGoogle Scholar
  36. 36.
    Aoki T, Kataoka H, Morimoto M, Nozaki K, Hashimoto N (2007) Macrophage-derived matrix metalloproteinase-2 and -9 promote the progression of cerebral aneurysms in rats. Stroke 38:162–169PubMedCrossRefGoogle Scholar
  37. 37.
    Kanematsu Y, Kanematsu M, Kurihara C, Tada Y, Tsou TL, van Rooijen N, Lawton MT, Young WL, Liang EI, Nuki Y, Hashimoto T (2011) Critical roles of macrophages in the formation of intracranial aneurysm. Stroke 42:173–178PubMedCentralPubMedCrossRefGoogle Scholar
  38. 38.
    Lee CH, Lin YH, Chang SH, Tai CD, Liu SJ, Chu Y, Wang CJ, Hsu MY, Chang H, Chang GJ, Hung KC, Hsieh MJ, Lin FC, Hsieh IC, Wen MS, Huang Y (2014) Local sustained delivery of acetylsalicylic acid via hybrid stent with biodegradable nanofibers reduces adhesion of blood cells and promotes reendothelialization of the denuded artery. Int J Nanomedicine 9:311–326PubMedCentralPubMedGoogle Scholar
  39. 39.
    Lee CH, Yu CY, Chang SH, Hung KC, Liu SJ, Wang CJ, Hsu MY, Hsieh IC, Chen WJ, Ko YS, Wen MS (2014) Promoting endothelial recovery and reducing neointimal hyperplasia using sequential-like release of acetylsalicylic acid and paclitaxel-loaded biodegradable stents. Int J Nanomedicine 9:4117–4133PubMedCentralPubMedCrossRefGoogle Scholar
  40. 40.
    Lin HL, Yen HW, Hsieh SL, An LM, Shen KP (2014) Low-dose aspirin ameliorated hyperlipidemia, adhesion molecule, and chemokine production induced by high-fat diet in Sprague-Dawley rats. Drug Develop Res 75:97–106CrossRefGoogle Scholar
  41. 41.
    Weber C, Erl W, Pietsch A, Weber PC (1995) Aspirin inhibits nuclear factor-kappa B mobilization and monocyte adhesion in stimulated human endothelial cells. Circulation 91:1914–1917PubMedCrossRefGoogle Scholar
  42. 42.
    Yang YY, Hu CJ, Chang SM, Tai TY, Leu SJ (2004) Aspirin inhibits monocyte chemoattractant protein-1 and interleukin-8 expression in TNF-alpha stimulated human umbilical vein endothelial cells. Atherosclerosis 174:207–213PubMedCrossRefGoogle Scholar
  43. 43.
    Dragomir E, Tircol M, Manduteanu I, Voinea M, Simionescu M (2006) Aspirin and PPAR-alpha activators inhibit monocyte chemoattractant protein-1 expression induced by high glucose concentration in human endothelial cells. Vascul Pharmacol 44:440–449PubMedCrossRefGoogle Scholar
  44. 44.
    Dai J, Louedec L, Philippe M, Michel JB, Houard X (2009) Effect of blocking platelet activation with AZD6140 on development of abdominal aortic aneurysm in a rat aneurysmal model. J Vasc Surg 49:719–727PubMedCrossRefGoogle Scholar
  45. 45.
    Fontaine V, Touat Z, Mtairag el M, Vranckx R, Louedec L, Houard X, Andreassian B, Sebbag U, Palombi T, Jacob MP, Meilhac O, Michel JB (2004) Role of leukocyte elastase in preventing cellular re-colonization of the mural thrombus. Am J Pathol 164:2077–2087PubMedCentralPubMedCrossRefGoogle Scholar
  46. 46.
    Whittle IR, Dorsch NW, Besser M (1982) Spontaneous thrombosis in giant intracranial aneurysms. J Neurol Neurosur Ps 45:1040–1047CrossRefGoogle Scholar
  47. 47.
    Cohen JE, Itshayek E, Gomori JM, Grigoriadis S, Raphaeli G, Spektor S, Rajz G (2007) Spontaneous thrombosis of cerebral aneurysms presenting with ischemic stroke. J Neurol Sci 254:95–98PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  • Shengjie Li
    • 1
  • Dehui Wang
    • 1
  • Ye Tian
    • 1
  • Huijie Wei
    • 1
  • Ziwei Zhou
    • 1
  • Li Liu
    • 1
  • Dong Wang
    • 1
  • Jing-fei Dong
    • 2
  • Rongcai Jiang
    • 1
  • Jianning Zhang
    • 1
  1. 1.Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin Neurological Institute, Key Laboratory of Post-trauma Neuro-repair and Regeneration in Central Nervous System, Ministry of Education, Tianjin Key Laboratory of InjuriesVariations and Regeneration of Nervous SystemTianjinPeople’s Republic of China
  2. 2.Puget Sound Blood Research InstituteSeattleUSA

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