We previously identified somatic activating mutations in the KRAS (Kirsten rat sarcoma viral oncogene homologue) gene in the endothelium of the majority of human sporadic brain arteriovenous malformations, a disorder characterized by direct connections between arteries and veins. However, whether this genetic abnormality alone is sufficient for lesion formation and how active KRAS signaling contributes to arteriovenous malformations remains unknown.
To establish the first in vivo models of somatic KRAS gain of function in the endothelium in both mice and zebrafish to directly observe the phenotypic consequences of constitutive KRAS activity at a cellular level in vivo and to test potential therapeutic interventions for arteriovenous malformations. Using both postnatal and adult mice and embryonic zebrafish, we demonstrate that endothelial-specific gain of function mutations in Kras (G12D or G12V) are sufficient to induce brain arteriovenous malformations. Furthermore, we show that these lesions are not associated with altered endothelial growth dynamics or a lack of true arteriovenous identity but instead seem to feature exuberant angiogenic signaling. Finally, we demonstrate that KRAS-dependent arteriovenous malformations in zebrafish are refractory to inhibit the downstream effector PI3K but instead require active MEK (mitogen-activated protein kinase kinase 1) signaling.
In conclusion, this study demonstrated that active KRAS expression in the endothelium is sufficient for arteriovenous brain malformations, even in the setting of uninjured adult vasculature. These findings provide new insight into sporadic bAVMs and offer hope that therapeutic approaches can be utilized to negate KRAS-mediated alterations in vessel morphology.