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Endogenous animal models of intracranial aneurysm development: a review

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Abstract

The pathogenesis and natural history of intracranial aneurysm (IA) remains poorly understood. To this end, animal models with induced cerebral vessel lesions mimicking human aneurysms have provided the ability to greatly expand our understanding. In this review, we comprehensively searched the published literature to identify studies that endogenously induced IA formation in animals. Studies that constructed aneurysms (i.e., by surgically creating a sac) were excluded. From the eligible studies, we reported information including the animal species, method for aneurysm induction, aneurysm definitions, evaluation methods, aneurysm characteristics, formation rate, rupture rate, and time course. Between 1960 and 2019, 174 articles reported endogenous animal models of IA. The majority used flow modification, hypertension, and vessel wall weakening (i.e., elastase treatment) to induce IAs, primarily in rats and mice. Most studies utilized subjective or qualitative descriptions to define experimental aneurysms and histology to study them. In general, experimental IAs resembled the pathobiology of the human disease in terms of internal elastic lamina loss, medial layer degradation, and inflammatory cell infiltration. After the early 2000s, many endogenous animal models of IA began to incorporate state-of-the-art technology, such as gene expression profiling and 9.4-T magnetic resonance imaging (MRI) in vivo imaging, to quantitatively analyze the biological mechanisms of IA. Future studies aimed at longitudinally assessing IA pathobiology in models that incorporate aneurysm growth will likely have the largest impact on our understanding of the disease. We believe this will be aided by high-resolution, small animal, survival imaging, in situ live-cell imaging, and next-generation omics technology.

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Acknowledgements

The authors would like to thank Liza Gutierrez, MD, LVT, at the Canon Stroke and Vascular Research Center for stimulating discussions during the drafting of this work.

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  1. Canon Stroke and Vascular Research Center, University at Buffalo - Clinical and Translational Research Center, State University of New York, Buffalo, NY, USA

    Vincent M. Tutino, Hamidreza Rajabzadeh-Oghaz, Sricharan S. Veeturi, Kerry E. Poppenberg, Muhammad Waqas, Max Mandelbaum, Nicholas Liaw, Adnan H. Siddiqui, Hui Meng & John Kolega

  2. Department of Neurosurgery, University at Buffalo, State University of New York, Buffalo, NY, USA

    Vincent M. Tutino, Hamidreza Rajabzadeh-Oghaz, Kerry E. Poppenberg & Muhammad Waqas

  3. Department of Pathology and Anatomical Sciences, University at Buffalo, State University of New York, Buffalo, NY, USA

    Vincent M. Tutino & John Kolega

  4. Department of Mechanical & Aerospace Engineering, University at Buffalo, State University of New York, Buffalo, NY, USA

    Vincent M. Tutino, Sricharan S. Veeturi, Max Mandelbaum, Nicholas Liaw & Hui Meng

  5. Department of Radiology, University at Buffalo, State University of New York, Buffalo, NY, USA

    Adnan H. Siddiqui

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Contributions

VMT, MM, NL, HM, and JK designed and conceived the article; VMT, HR-O, SSV, KEP, MM, and NL acquired the data; VMT, HR-O, MM, NL, and JK analyzed and interpreted the data; VMT, HR-O, MM, NL, HM, and JK drafted the article; VMT, HR-O, KEP, MW, AHS, MM, NL, HM, and JK critically revised the manuscript; all authors approved the article.

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Correspondence to Vincent M. Tutino.

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Competing interests

VMT—Principal investigator: National Science Foundation Award No. 1746694, NIH NINDS award R43 NS115314-0, Clinical and Translational Science Institute grant. Co-founder: Neurovascular Diagnostics, Inc.

AHS—Financial Interest/Investor/Stock Options/Ownership: Amnis Therapeutics, Apama Medical, BlinkTBI, Inc, Buffalo Technology Partners, Inc., Cardinal Health, Cerebrotech Medical Systems, Inc, Claret Medical, Cognition Medical, Endostream Medical, Ltd, Imperative Care, International Medical Distribution Partners, Rebound Therapeutics Corp., Silk Road Medical, StimMed, Synchron, Three Rivers Medical, Inc., Viseon Spine, Inc. Consultant/Advisory Board: Amnis Therapeutics, Boston Scientific, Canon Medical Systems USA, Inc., Cerebrotech Medical Systems, Inc., Cerenovus, Claret Medical, Corindus, Inc., Endostream Medical, Ltd, Guidepoint Global Consulting, Imperative Care, Integra, Medtronic, Micro- Vention, Northwest University—DSMB Chair for HEAT Trial, Penumbra, Rapid Medical, Rebound Therapeutics Corp., Silk Road Medical, StimMed, Stryker, Three Rivers Medical, Inc., VasSol, W.L. Gore & Associates. National PI/Steering Committees: Cerenovus LARGE Trial and ARISE II Trial, Medtronic SWIFT PRIME and SWIFT DIRECT Trials, MicroVention FRED Trial & CONFIDENCE Study, MUSC POSITIVE Trial, Penumbra 3D Separator Trial, COMPASS Trial, INVEST Trial. Principal investigator: Cummings Foundation grant.

HM—Principal investigator NIH grant R01NS064592 and NIH grant R01NS091075. Co-founder: Neurovascular Diagnostics, Inc.

HR-O, SSV, KEP, MW, MM, NL, JK declare no competing interests.

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Tutino, V.M., Rajabzadeh-Oghaz, H., Veeturi, S.S. et al. Endogenous animal models of intracranial aneurysm development: a review. Neurosurg Rev 44, 2545–2570 (2021). https://doi.org/10.1007/s10143-021-01481-w

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