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Map3k3I441M knock-in mouse model of cerebral cavernous malformations
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1 State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing,
China
Brain & Heart, 025150019 https://doi.org/10.36922/BH025150019
Received: 11 April 2025 | Revised: 22 June 2025 | Accepted: 8 July 2025 | Published online: 13 August 2025
© 2025 by the Author(s). This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution 4.0 International License ( https://creativecommons.org/licenses/by/4.0/ )
Abstract
The Map3k3I441M knock-in mouse model reveals an age-dependent mechanism in cerebral cavernous malformation (CCM) pathogenesis, wherein PI3K pathway activation is required for lesion formation in adults but not juveniles. Notably, rapamycin treatment effectively inhibited lesions across age groups, underscoring mammalian target of rapamycin (mTOR) inhibition as a potential therapy. This commentary highlights mechanistic insights from the Map3k3I441M knock-in mouse model, emphasizing the age-dependent role of PI3K signaling in CCM formation. It discusses the potential synergy between MAP3K3 and PIK3CA mutations, explores the therapeutic potential of mTOR inhibition, and considers the potential influence of pre-conceptional environmental exposures on CCM susceptibility.
Keywords
Cerebral cavernous malformations
Map3k3 mutation
Mouse model
Funding
This study was supported by the Chinese Academy of Medical Sciences, Innovation Fund for Medical Sciences (grants no.: 2023-CXGC-SYS01-2 and 2021-I2M-1-016), National Natural Science Foundation of China (grant no.:82470450), the National High Level Hospital Clinical Research Funding Grant (grant no.:2025-GSP-GG-29), and the State Key Laboratory of Cardiovascular Disease.
Conflict of interest
Yibo Wang is an Editorial Board Member of this journal, but was not in any way involved in the editorial and peer-review process conducted for this paper, directly or indirectly. Separately, other authors declared that they have no known competing financial interests or personal relationships that could have influenced the work reported in this paper.
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