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Novel Murine Models of Cerebral Cavernous Malformations

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Abstract

Cerebral cavernous malformations (CCMs) are ectatic capillary-venous malformations that develop in approximately 0.5% of the population. Patients with CCMs may develop headaches, focal neurologic deficits, seizures, and hemorrhages. While symptomatic CCMs, depending upon the anatomic location, can be surgically removed, there is currently no pharmaceutical therapy to treat CCMs. Several mouse models have been developed to better understand CCM pathogenesis and test therapeutics. The most common mouse models induce a large CCM burden that is anatomically restricted to the cerebellum and contributes to lethality in the early days of life. These inducible models thus have a relatively short period for drug administration. We developed an inducible CCM3 mouse model that develops CCMs after weaning and provides a longer period for potential therapeutic intervention. Using this new model, three recently proposed CCM therapies, fasudil, tempol, vitamin D3, and a combination of the three drugs, failed to substantially reduce CCM formation when treatment was administered for 5 weeks, from postnatal day 21 (P21) to P56. We next restricted Ccm3 deletion to the brain vasculature and provided greater time (121 days) for CCMs to develop chronic hemorrhage, recapitulating the human lesions. We also developed the first model of acute CCM hemorrhage by injecting mice harboring CCMs with lipopolysaccharide. These efficient models will enable future drug studies to more precisely target clinically relevant features of CCM disease: CCM formation, chronic hemorrhage, and acute hemorrhage.

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Acknowledgements

The authors would like to thank Drs. Wang Min, Marcus Fruttiger, and Markus Schwaninger for generously providing transgenic mice used in this work. We would also like to thank Drs. Mark Kahn and Mark Ginsberg for helpful discussions.

Funding

This work was supported by the National Institutes of Health (P01 NS092521 to D.A. Marchuk and I.A. Awad, F30 HL140871 to M.R. Detter, and T32 GM007171), the Fondation Leducq (17 CVD 03 to D.A. Marchuk), and the American Heart Association (18PRE34060061 to M.R. Detter).

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Author notes

  1. Issam A. Awad and Douglas A. Marchuk contributed equally to this study.

Authors and Affiliations

  1. Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, NC, 27705, USA

    Matthew R. Detter, Christian R. Benavides, Catherine A. Neilson, Erin Griffin, Carol J. Gallione & Douglas A. Marchuk

  2. Neurovascular Surgery Program, Department of Neurosurgery, University of Chicago Medicine and Biological Sciences, Chicago, IL, 60637, USA

    Robert Shenkar, Thomas Moore, Rhonda Lightle, Nicholas Hobson, Le Shen, Ying Cao, Romuald Girard, Dongdong Zhang & Issam A. Awad

  3. James B Duke Professor, Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Box 3175, Durham, NC, 27710, USA

    Douglas A. Marchuk

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  1. Matthew R. Detter
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Detter, M.R., Shenkar, R., Benavides, C.R. et al. Novel Murine Models of Cerebral Cavernous Malformations. Angiogenesis 23, 651–666 (2020). https://doi.org/10.1007/s10456-020-09736-8

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