Cerebral Cavernous Malformation: From Genetics to Pharmacotherapy

Abstract

Introduction: Cerebral cavernous malformation (CCM) is a type of cerebrovascular abnormality in the central nervous system linked to both germline and somatic genetic mutations. Recent preclinical and clinical studies have shown that various drugs can effectively reduce the burden of CCM lesions. Despite significant progress, the mechanisms driving CCM remain incompletely understood, and to date, no drugs have been developed that can cure or prevent CCM. This review aims to explore the genetic mutations, molecular mechanisms, and pharmacological interventions related to CCM.

Methods: Literatures on the genetic mechanisms and pharmacological treatments of CCM can be searched in PubMed and Web of Science.

Results: Germline and somatic mutations mediate the onset and development of CCM through several molecular pathways. Medications such as statins, fasudil, rapamycin, and propranolol can alleviate CCM symptoms or hinder its progression by specifically modulating the corresponding targets.

Conclusions: Understanding the molecular mechanisms underlying CCM offers potential for targeted therapies. Further research into novel mutations and treatment strategies is essential for improving patient outcomes.

Keywords: cerebral cavernous malformation; germline mutation; pharmacotherapy; somatic mutation.

FIGURE 1

Non‐enhanced brain MRI of familial CCM and sporadic CCM. (A) T1, (B) FLAIR, and (C) SWI sequences of a familial CCM patient with multiple lesions in the pons, cerebellum, and temporal lobe (arrows). (D) T1, (E) FLAIR, and (F) SWI sequences of a sporadic CCM patient with a single lesion in the temporal lobe (arrows).

FIGURE 2

Schematic overview of the cellular and molecular features of cerebral cavernous malformation.

FIGURE 3

Key signaling pathways in the pathogenesis of CCM. CCM1, CCM2, and CCM3 encode proteins that form the CCM protein complex, which plays a critical role in vascular stability. The complex's upstream regulation is influenced by the interaction with LPS through binding to TLR4 and CD14. In familial CCM, loss‐of‐function mutations in the CCM gene deregulate the inhibitory effect on downstream RhoA, which in turn activates the RhoA–ROCK signaling pathway and promotes cell migration, deletion of intercellular junctions, and stress fiber formation. Moreover, loss‐of‐function mutations in the CCM genes or somatic gain‐of‐function mutations in the MAP3K3 gene activate the MAP3K3–KLF2/4 signaling pathway, which drives EndMT, angiogenesis, and oxidative stress. In addition, somatic gain‐of‐function mutations in PIK3CA lead to activation of the PI3K–AKT signaling pathway, resulting in abnormal cell proliferation, increased inflammation, and impaired autophagy.