Journal
HUMAN MOLECULAR GENETICS
Volume -, Issue -, Pages -Publisher
OXFORD UNIV PRESS
DOI: 10.1093/hmg/ddac169
Keywords
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Funding
- Fonds de la Recherche Scientifique-FNRS [T.0026.14, T.0247.19, T.0146.16, P.C013.20]
- King Baudouin Foundation
- Pierre M. fellowship
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The study reports the association between KRAS mutations and arteriovenous malformations. By activating KRAS in vascular endothelial cells using a mouse model, the researchers successfully generated an arteriovenous malformation mouse model. They also found that trametinib could effectively slow down the progression of the lesions and has the potential to be a therapeutic option for KRAS-induced vascular malformations.
Somatic activating Kirsten rat sarcoma viral oncogene homologue (KRAS) mutations have been reported in patients with arteriovenous malformations. By producing LSL-Kras (G12D); Cdh5 (PAC)-CreERT2 [iEC-Kras (G12D*)] mice, we hoped to activate KRAS within vascular endothelial cells (ECs) to generate an arteriovenous malformation mouse model. Neonatal mice were treated daily with tamoxifen from postnatal (PN) days 1-3. Mortality and phenotypes varied amongst iEC-Kras (G12D*) pups, with only 31.5% surviving at PN14. Phenotypes (focal lesions, vessel dilations) developed in a consistent manner, although with unpredictable severity within multiple soft tissues (such as the brain, liver, heart and brain). Overall, iEC-Kras (G12D*) pups developed significantly larger vascular lumen areas compared with control littermates, beginning at PN8. We subsequently tested whether the MEK inhibitor trametinib could effectively alleviate lesion progression. At PN16, iEC-Kras (G12D*) pup survival improved to 76.9%, and average vessel sizes were closer to controls than in untreated and vehicle-treated mutants. In addition, trametinib treatment helped normalize iEC-Kras (G12D*) vessel morphology in PN14 brains. Thus, trametinib could act as an effective therapy for KRAS-induced vascular malformations in patients.
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