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Review

Cerebral Cavernous Malformation Pathogenesis: Investigating Lesion Formation and Progression with Animal Models

by
Chelsea M. Phillips
1,
Svetlana M. Stamatovic
2,
Richard F. Keep
3,4 and
Anuska V. Andjelkovic
2,3,*
1
Neuroscience Graduate Program, University of Michigan Medical School, Ann Arbor, MI 48109, USA
2
Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA
3
Department of Neurosurgery, University of Michigan Medical School, Ann Arbor, MI 48109, USA
4
Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI 48109, USA
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2022, 23(9), 5000; https://doi.org/10.3390/ijms23095000
Submission received: 8 April 2022 / Revised: 25 April 2022 / Accepted: 28 April 2022 / Published: 30 April 2022
(This article belongs to the Special Issue Molecular Mechanisms of Cerebrovascular Diseases)

Abstract

Cerebral cavernous malformation (CCM) is a cerebromicrovascular disease that affects up to 0.5% of the population. Vessel dilation, decreased endothelial cell–cell contact, and loss of junctional complexes lead to loss of brain endothelial barrier integrity and hemorrhagic lesion formation. Leakage of hemorrhagic lesions results in patient symptoms and complications, including seizures, epilepsy, focal headaches, and hemorrhagic stroke. CCMs are classified as sporadic (sCCM) or familial (fCCM), associated with loss-of-function mutations in KRIT1/CCM1, CCM2, and PDCD10/CCM3. Identifying the CCM proteins has thrust the field forward by (1) revealing cellular processes and signaling pathways underlying fCCM pathogenesis, and (2) facilitating the development of animal models to study CCM protein function. CCM animal models range from various murine models to zebrafish models, with each model providing unique insights into CCM lesion development and progression. Additionally, these animal models serve as preclinical models to study therapeutic options for CCM treatment. This review briefly summarizes CCM disease pathology and the molecular functions of the CCM proteins, followed by an in-depth discussion of animal models used to study CCM pathogenesis and developing therapeutics.
Keywords: cerebrovascular malformation; KRIT1; CCM2; PDCD10; hemorrhagic lesions; CCM animal models; RhoA kinase inhibition cerebrovascular malformation; KRIT1; CCM2; PDCD10; hemorrhagic lesions; CCM animal models; RhoA kinase inhibition

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MDPI and ACS Style

Phillips, C.M.; Stamatovic, S.M.; Keep, R.F.; Andjelkovic, A.V. Cerebral Cavernous Malformation Pathogenesis: Investigating Lesion Formation and Progression with Animal Models. Int. J. Mol. Sci. 2022, 23, 5000. https://doi.org/10.3390/ijms23095000

AMA Style

Phillips CM, Stamatovic SM, Keep RF, Andjelkovic AV. Cerebral Cavernous Malformation Pathogenesis: Investigating Lesion Formation and Progression with Animal Models. International Journal of Molecular Sciences. 2022; 23(9):5000. https://doi.org/10.3390/ijms23095000

Chicago/Turabian Style

Phillips, Chelsea M., Svetlana M. Stamatovic, Richard F. Keep, and Anuska V. Andjelkovic. 2022. "Cerebral Cavernous Malformation Pathogenesis: Investigating Lesion Formation and Progression with Animal Models" International Journal of Molecular Sciences 23, no. 9: 5000. https://doi.org/10.3390/ijms23095000

APA Style

Phillips, C. M., Stamatovic, S. M., Keep, R. F., & Andjelkovic, A. V. (2022). Cerebral Cavernous Malformation Pathogenesis: Investigating Lesion Formation and Progression with Animal Models. International Journal of Molecular Sciences, 23(9), 5000. https://doi.org/10.3390/ijms23095000

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