Animal Models of Intracranial Aneurysms

  • Elena I. Liang
  • Hiroshi Makino
  • Yoshiteru Tada
  • Kosuke Wada
  • Tomoki Hashimoto
Part of the Springer Series in Translational Stroke Research book series (SSTSR)


We established a new mouse model of intracranial aneurysms that yields large aneurysms within a relatively short time frame. Aneurysms are induced by a combination of pharmacological hypertension and a single injection of elastase into the cerebrospinal fluid. The model gives us a unique opportunity to study and understand the mechanisms for not only aneurysm formation but also the rupture of intracranial aneurysms. Using this model, we can study the effects of various pharmacological agents on aneurysmal rupture in mice and translate our findings toward the clinical setting.


Intracranial Aneurysm Aneurysmal Subarachnoid Hemorrhage Unruptured Aneurysm Aneurysmal Rupture Aneurysm Induction 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



This study was funded by the National Institutes of Health (R01NS055876 P01NS04415, both TH), the American Heart Association (11GRNT6380003, TH), and The Brain Aneurysm Foundation (TH).


  1. 1.
    Schievink WI. Intracranial aneurysms. N Engl J Med. 1997;336:28–40.PubMedCrossRefGoogle Scholar
  2. 2.
    Juvela S. Treatment options of unruptured intracranial aneurysms. Stroke. 2004;35:372–4.PubMedCrossRefGoogle Scholar
  3. 3.
    Wiebers DO, Whisnant JP, Huston III J, Meissner I, Brown Jr RD, Piepgras DG, Forbes GS, Thielen K, Nichols D, O’Fallon WM, Peacock J, Jaeger L, Kassell NF, Kongable-Beckman GL, Torner JC. Unruptured intracranial aneurysms: Natural history, clinical outcome, and risks of surgical and endovascular treatment. Lancet. 2003;362:103–10.PubMedCrossRefGoogle Scholar
  4. 4.
    Hoi Y, Meng H, Woodward SH, Bendok BR, Hanel RA, Guterman LR, Hopkins LN. Effects of arterial geometry on aneurysm growth: three-dimensional computational fluid dynamics study. J Neurosurg. 2004;101:676–81.PubMedCrossRefGoogle Scholar
  5. 5.
    German WJ, Black SP. Experimental production of carotid aneurysms. N Engl J Med. 1954;250:104–6.PubMedCrossRefGoogle Scholar
  6. 6.
    Guglielmi G, Ji C, Massoud TF, Kurata A, Lownie SP, Vinuela F, Robert J. Experimental saccular aneurysms. II. A new model in swine. Neuroradiology. 1994;36:547–50.PubMedCrossRefGoogle Scholar
  7. 7.
    Massoud TF, Ji C, Guglielmi G, Vinuela F, Robert J. Experimental models of bifurcation and terminal aneurysms: construction techniques in swine. AJNR Am J Neuroradiol. 1994;15:938–44.PubMedGoogle Scholar
  8. 8.
    Graves VB, Ahuja A, Strother CM, Rappe AH. Canine model of terminal arterial aneurysm. AJNR Am J Neuroradiol. 1993;14:801–3.PubMedGoogle Scholar
  9. 9.
    Macdonald RL, Mojtahedi S, Johns L, Kowalczuk A. Randomized comparison of guglielmi detachable coils and cellulose acetate polymer for treatment of aneurysms in dogs. Stroke. 1998;29:478–85; discussion 485–86.Google Scholar
  10. 10.
    Forrest MD, O’Reilly GV. Production of experimental aneurysms at a surgically created arterial bifurcation. AJNR Am J Neuroradiol. 1989;10:400–2.PubMedGoogle Scholar
  11. 11.
    Cloft HJ, Altes TA, Marx WF, Raible RJ, Hudson SB, Helm GA, Mandell JW, Jensen ME, Dion JE, Kallmes DF. Endovascular creation of an in vivo bifurcation aneurysm model in rabbits. Radiology. 1999;213:223–8.PubMedGoogle Scholar
  12. 12.
    Altes TA, Cloft HJ, Short JG, DeGast A, Do HM, Helm GA, et al. 1999 arrs executive council award. Creation of saccular aneurysms in the rabbit: a model suitable for testing endovascular devices. American Roentgen Ray Society. AJR Am J Roentgenol. 2000;174:349–54.Google Scholar
  13. 13.
    Cawley CM, Dawson RC, Shengelaia G, Bonner G, Barrow DL, Colohan AR. Arterial saccular aneurysm model in the rabbit. AJNR Am J Neuroradiol. 1996;17:1761–6.PubMedGoogle Scholar
  14. 14.
    Kallmes DF, Fujiwara NH, Berr SS, Helm GA, Cloft HJ. Elastase-induced saccular aneurysms in rabbits: a dose-escalation study. AJNR Am J Neuroradiol. 2002;23:295–8.PubMedGoogle Scholar
  15. 15.
    Yasuno K, Bilguvar K, Bijlenga P, Low SK, Krischek B, Auburger G, Simon M, Krex D, Arlier Z, Nayak N, Ruigrok YM, Niemela M, Tajima A, Von und zu Fraunberg M, Doczi T, Wirjatijasa F, Hata A, Blasco J, Oszvald A, Kasuya H, Zilani G, Schoch B, Singh P, Stuer C, Risselada R, Beck J, Sola T, Ricciardi F, Aromaa A, Illig T, Schreiber S, van Duijn CM, Van den Berg LH, Perret C, Proust C, Roder C, Ozturk AK, Gaal E, Berg D, Geisen C, Friedrich CM, Summers P, Frangi AF, State MW, Wichmann HE, Breteler MM, Wijmenga C, Mane S, Peltonen L, Elio V, Sturkenboom MC, Lawford P, Byrne J, Macho J, Sandalcioglu EI, Meyer B, Raabe A, Steinmetz H, Rufenacht D, Jaaskelainen JE, Hernesniemi J, Rinkel GJ, Zembutsu H, Inoue I, Palotie A, Cambien F, Nakamura Y, Lifton RP, Gunel M. Genome-wide association study of intracranial aneurysm identifies three new risk loci. Nat Genet. 2010;42:420–5.PubMedCrossRefGoogle Scholar
  16. 16.
    Nahed BV, Bydon M, Ozturk AK, Bilguvar K, Bayrakli F, Gunel M. Genetics of intracranial aneurysms. Neurosurgery. 2007;60:213–25; discussion 225–26.Google Scholar
  17. 17.
    Hashimoto N, Handa H, Hazama F. Experimentally induced cerebral aneurysms in rats. Surg Neurol. 1978;10:3–8.PubMedGoogle Scholar
  18. 18.
    Hashimoto N, Handa H, Hazama F. Experimentally induced cerebral aneurysms in rats: part II. Surg Neurol. 1979;11:243–6.PubMedGoogle Scholar
  19. 19.
    Hashimoto N, Kim C, Kikuchi H, Kojima M, Kang Y, Hazama F. Experimental induction of cerebral aneurysms in monkeys. J Neurosurg. 1987;67:903–5.PubMedCrossRefGoogle Scholar
  20. 20.
    Morimoto M, Miyamoto S, Mizoguchi A, Kume N, Kita T, Hashimoto N. Mouse model of cerebral aneurysm: experimental induction by renal hypertension and local hemodynamic changes. Stroke. 2002;33:1911–5.PubMedCrossRefGoogle Scholar
  21. 21.
    Hashimoto N, Handa H, Nagata I, Hazama F. Experimentally induced cerebral aneurysms in rats: Part V. Relation of hemodynamics in the circle of Willis to formation of aneurysms. Surg Neurol. 1980;13:41–5.PubMedGoogle Scholar
  22. 22.
    Yang G, Kitagawa K, Matsushita K, Mabuchi T, Yagita Y, Yanagihara T, Matsumoto M. C57bl/6 strain is most susceptible to cerebral ischemia following bilateral common carotid occlusion among seven mouse strains: selective neuronal death in the murine transient forebrain ischemia. Brain Res. 1997;752:209–18.PubMedCrossRefGoogle Scholar
  23. 23.
    Okuyama S, Okuyama J, Tamatsu Y, Shimada K, Hoshi H, Iwai J. The arterial circle of Willis of the mouse helps to decipher secrets of cerebral vascular accidents in the human. Med Hypotheses. 2004;63:997–1009.PubMedCrossRefGoogle Scholar
  24. 24.
    Beckmann N. High resolution magnetic resonance angiography non-invasively reveals mouse strain differences in the cerebrovascular anatomy in vivo. Magn Reson Med. 2000;44:252–8.PubMedCrossRefGoogle Scholar
  25. 25.
    McColl BW, Carswell HV, McCulloch J, Horsburgh K. Extension of cerebral hypoperfusion and ischaemic pathology beyond mca territory after intraluminal filament occlusion in C57Bl/6J mice. Brain Res. 2004;997:15–23.PubMedCrossRefGoogle Scholar
  26. 26.
    Aoki T, Kataoka H, Ishibashi R, Nozaki K, Egashira K, Hashimoto N. Impact of monocyte chemoattractant protein-1 deficiency on cerebral aneurysm formation. Stroke. 2009;40:942–51.PubMedCrossRefGoogle Scholar
  27. 27.
    Moriwaki T, Takagi Y, Sadamasa N, Aoki T, Nozaki K, Hashimoto N. Impaired progression of cerebral aneurysms in interleukin-1beta-deficient mice. Stroke. 2006;37:900–5.PubMedCrossRefGoogle Scholar
  28. 28.
    Nuki Y, Tsou TL, Kurihara C, Kanematsu M, Kanematsu Y, Hashimoto T. Elastase-induced intracranial aneurysms in hypertensive mice. Hypertension. 2009;54:1337–44.PubMedCrossRefGoogle Scholar
  29. 29.
    Kanematsu Y, Kanematsu M, Kurihara C, Tada Y, Tsou TL, van Rooijen N, Lawton MT, Young WL, Liang EI, Nuki Y, Hashimoto T. Critical roles of macrophages in the formation of intracranial aneurysm. Stroke. 2011;42:173–8.PubMedCrossRefGoogle Scholar
  30. 30.
    Tada Y, Kanematsu Y, Kanematsu M, Nuki Y, Liang EI, Wada K, et al. A mouse model of intracranial aneurysm: technical considerations. Acta Neurochir Suppl. 2011;111:31–5.PubMedCrossRefGoogle Scholar
  31. 31.
    Connolly Jr ES, Choudhri TF, Mack WJ, Mocco J, Spinks TJ, Slosberg J, Lin T, Huang J, Solomon RA. Influence of smoking, hypertension, and sex on the phenotypic expression of familial intracranial aneurysms in siblings. Neurosurgery. 2001;48:64–8.PubMedGoogle Scholar
  32. 32.
    Bonita R. Cigarette smoking, hypertension and the risk of subarachnoid hemorrhage: a population-based case–control study. Stroke. 1986;17:831–5.PubMedCrossRefGoogle Scholar
  33. 33.
    Cajander S, Hassler O. Enzymatic destruction of the elastic lamella at the mouth of cerebral berry aneurysm? An ultrastructural study with special regard to the elastic tissue. Acta Neurol Scand. 1976;53:171–81.PubMedCrossRefGoogle Scholar
  34. 34.
    Weiss D, Taylor WR. Deoxycorticosterone acetate salt hypertension in apolipoprotein E−/− mice results in accelerated atherosclerosis: the role of angiotensin II. Hypertension. 2008;51:218–24.PubMedCrossRefGoogle Scholar
  35. 35.
    Kanematsu Y, Kanematsu M, Kurihara C, Tsou TL, Nuki Y, Liang EI, Makino H, Hashimoto T. Pharmacologically induced thoracic and abdominal aortic aneurysms in mice. Hypertension. 2010;55:1267–74.PubMedCrossRefGoogle Scholar
  36. 36.
    Huang Z, Huang PL, Panahian N, Dalkara T, Fishman MC, Moskowitz MA. Effects of cerebral ischemia in mice deficient in neuronal nitric oxide synthase. Science. 1994;265:1883–5.PubMedCrossRefGoogle Scholar
  37. 37.
    Yang G, Chan PH, Chen J, Carlson E, Chen SF, Weinstein P, Epstein CJ, Kamii H. Human copper-zinc superoxide dismutase transgenic mice are highly resistant to reperfusion injury after focal cerebral ischemia. Stroke. 1994;25:165–70.PubMedCrossRefGoogle Scholar
  38. 38.
    Chan PH. Oxygen radicals in focal cerebral ischemia. Brain Pathol. 1994;4:59–65.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  • Elena I. Liang
    • 1
  • Hiroshi Makino
    • 1
  • Yoshiteru Tada
    • 1
  • Kosuke Wada
    • 1
  • Tomoki Hashimoto
    • 1
  1. 1.Department of Anesthesia and Perioperative Care, Center for Cerebrovascular ResearchUniversity of CaliforniaSan FranciscoUSA

Personalised recommendations