Selective Endothelial Hyperactivation of Oncogenic KRAS Induces Brain Arteriovenous Malformations in Mice.

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. 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. 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. 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.

Park ES ，Kim S ，Huang S ，Yoo JY ，Körbelin J ，Lee TJ ，Kaur B ，Dash PK ，Chen PR ，Kim E ... -  《-》

Somatic mosaicism in the MAPK pathway in sporadic brain arteriovenous malformation and association with phenotype.

Gao S ，Nelson J ，Weinsheimer S ，Winkler EA ，Rutledge C ，Abla AA ，Gupta N ，Shieh JT ，Cooke DL ，Hetts SW ，Tihan T ，Hess CP ，Ko N ，Walcott BP ，McCulloch CE ，Lawton MT ，Su H ，Pawlikowska L ，Kim H ... -  《-》

Somatic Gain of KRAS Function in the Endothelium Is Sufficient to Cause Vascular Malformations That Require MEK but Not PI3K Signaling.

Fish JE ，Flores Suarez CP ，Boudreau E ，Herman AM ，Gutierrez MC ，Gustafson D ，DiStefano PV ，Cui M ，Chen Z ，De Ruiz KB ，Schexnayder TS ，Ward CS ，Radovanovic I ，Wythe JD ... -  《-》

KRAS G12D or G12V Mutation in Human Brain Arteriovenous Malformations.

Brain arteriovenous malformations (BAVMs) are vascular malformations composed of tangles of abnormally developed vasculature without capillaries. Abnormal shunting of arteries and veins is formed, resulting in high-pressure vascular channels, which potentially lead to rupture. BAVMs are generally considered a congenital disorder. But clinical evidence regarding involution, regrowth, and de novo formation argue against the static condition of this disease. Recently, the presence of the somatic activating KRAS mutations in more than half of BAVM cases was reported, suggesting the role of KRAS function in the pathogenesis. KRAS mutation in codon35 (G→A, G12D; G→T, G12V) was examined by a digital polymerase chain reaction analysis using genome purified from paraffin-embedded slides of human BAVMs. We also examined protein expression of KRAS G12D in lesions to corroborate results from digital polymerase chain reaction analysis. We detected codon35 G→A mutation in 15 (39.5%) among 38 samples and codon35 G→T mutation in 10 (27.0%) among 37 samples we could assess mutations. There were no samples positive for both codon35 G→A and G→T mutation. The ratio of codon35 G→A mutation ranged from 0.60% to 12.28% and that of G→T was from 1.20% to 8.99%. We next examined protein expression of KRAS G12D in BAVM lesions in immunohistochemistry. A KRAS G12D mutant was detected mainly in endothelial cells of dilated vessels in lesions. KRAS mutations in codon35 were detected in about two thirds of specimens examined. KRAS function may actively contribute to the pathobiology of BAVM and can become a therapeutic target.

Oka M ，Kushamae M ，Aoki T ，Yamaguchi T ，Kitazato K ，Abekura Y ，Kawamata T ，Mizutani T ，Miyamoto S ，Takagi Y ... -  《-》

Somatic Activating KRAS Mutations in Arteriovenous Malformations of the Brain.

Nikolaev SI ，Vetiska S ，Bonilla X ，Boudreau E ，Jauhiainen S ，Rezai Jahromi B ，Khyzha N ，DiStefano PV ，Suutarinen S ，Kiehl TR ，Mendes Pereira V ，Herman AM ，Krings T ，Andrade-Barazarte H ，Tung T ，Valiante T ，Zadeh G ，Tymianski M ，Rauramaa T ，Ylä-Herttuala S ，Wythe JD ，Antonarakis SE ，Frösen J ，Fish JE ，Radovanovic I ... -  《-》