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Selective Endothelial Hyperactivation of Oncogenic<scp>KRAS</scp>Induces Brain Arteriovenous Malformations in Mice
- Source :
- Annals of Neurology. 89:926-941
- Publication Year :
- 2021
- Publisher :
- Wiley, 2021.
-
Abstract
- Objective Brain arteriovenous malformations (bAVMs) are a leading cause of hemorrhagic stroke and neurological deficits in children and young adults, however, no pharmacological intervention is available to treat these patients. Although more than 95% of bAVMs are sporadic without family history, the pathogenesis of sporadic bAVMs is largely unknown, which may account for the lack of therapeutic options. KRAS mutations are frequently observed in cancer, and a recent unprecedented finding of these mutations in human sporadic bAVMs offers a new direction in the bAVM research. Using a novel adeno-associated virus targeting brain endothelium (AAV-BR1), the current study tested if endothelial KRASG12V mutation induces sporadic bAVMs in mice. Methods Five-week-old mice were systemically injected with either AAV-BR1-GFP or -KRASG12V . At 8 weeks after the AAV injection, bAVM formation and characteristics were addressed by histological and molecular analyses. The effect of MEK/ERK inhibition on KRASG12V -induced bAVMs was determined by treatment of trametinib, a US Food and Drug Administration (FDA)-approved MEK/ERK inhibitor. Results The viral-mediated KRASG12V overexpression induced bAVMs, which were composed of a tangled nidus mirroring the distinctive morphology of human bAVMs. The bAVMs were accompanied by focal angiogenesis, intracerebral hemorrhages, altered vascular constituents, neuroinflammation, and impaired sensory/cognitive/motor functions. Finally, we confirmed that bAVM growth was inhibited by trametinib treatment. Interpretation Our innovative approach using AAV-BR1 confirms that KRAS mutations promote bAVM development via the MEK/ERK pathway, and provides a novel preclinical mouse model of bAVMs which will be useful to develop a therapeutic strategy for patients with bAVM. ANN NEUROL 2021;89:926-941.
- Subjects :
- Intracranial Arteriovenous Malformations
0301 basic medicine
MAPK/ERK pathway
Pyridones
Angiogenesis
Pyrimidinones
medicine.disease_cause
Proto-Oncogene Proteins p21(ras)
Pathogenesis
Mice
03 medical and health sciences
Cognition
0302 clinical medicine
Animals
Humans
Medicine
Extracellular Signal-Regulated MAP Kinases
Neuroinflammation
Trametinib
Mutation
Neovascularization, Pathologic
business.industry
Cancer
Dependovirus
medicine.disease
Magnetic Resonance Imaging
030104 developmental biology
Gene Expression Regulation
Neurology
Cancer research
Encephalitis
Endothelium, Vascular
Neurology (clinical)
KRAS
business
Intracranial Hemorrhages
Psychomotor Performance
030217 neurology & neurosurgery
Subjects
Details
- ISSN :
- 15318249 and 03645134
- Volume :
- 89
- Database :
- OpenAIRE
- Journal :
- Annals of Neurology
- Accession number :
- edsair.doi.dedup.....27fdd931aefccc5cfd88506a60b42166