Somatic Gain of KRAS Function in the Endothelium is Sufficient to Cause Vascular Malformations that Require MEK but not PI3K Signaling

ABSTRACT: Rationale – We previously identified somatic activating mutations in the KRAS gene in the endothelium of the majority of human sporadic brain arteriovenous malformations (bAVMs); a disorder characterized by direct connections between arteries and veins. However, whether this genetic abnormality alone is sufficient for lesion formation, as well as how active KRAS signaling contributes to AVM formation, remains unknown. Objective – To establish the first in vivo models of somatic KRAS gain of function in the endothelium in both mice and zebrafish in order to directly observe the phenotypic consequences of constitutive KRAS activity at a cellular level in vivo, and to test potential therapeutic interventions for AVMs. Methods and Results – Using both postnatal and adult mice, as well as embryonic zebrafish, we demonstrate that endothelial-specific gain of function mutations in Kras (G12D or G12V) are sufficient to induce bAVMs. Active KRAS signaling leads to altered endothelial cell morphogenesis and increased cell size, ectopic sprouting, expanded vessel lumen diameter, and direct connections between arteries and veins. Furthermore, we show that these lesions are not associated with altered endothelial growth dynamics or a lack of proper arteriovenous identity, but instead appear to feature exuberant angiogenic signaling. Finally, we demonstrate that KRAS-dependent AVMs in zebrafish are refractory to inhibition of the downstream effector PI3K, but instead require active MEK signaling. Conclusions – We demonstrate that active KRAS expression in the endothelium is sufficient for bAVM formation, even in the setting of uninjured adult vasculature. Furthermore, the finding that KRAS-dependent lesions are reversible in zebrafish suggests that MEK inhibition may represent a promising therapeutic treatment for AVM patients.

ORGANISM(S): Homo sapiens

PROVIDER: GSE150426 | GEO | 2020/07/01

REPOSITORIES: GEO