Selective Endothelial Hyperactivation of OncogenicKRAS Induces Brain Arteriovenous Malformations in Mice
| Autor: | Pramod K. Dash, Eunhee Kim, Peng R Chen, Shuning Huang, Eun Sook Park, Jakob Körbelin, Tae Jin Lee, Balveen Kaur, Sehee Kim, Ji Young Yoo |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
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 |
| Zdroj: | Annals of Neurology. 89:926-941 |
| ISSN: | 1531-8249 0364-5134 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Plný text