KRAS-Dependent Glycolytic Reprogramming of Endothelial Cells in Sporadic Arteriovenous Malformations

Brain arteriovenous malformation (bAVM) is a disease characterized by the formation of tangled blood vessels with direct connections between arteries and veins. There is currently limited understanding of the underlying molecular mechanisms that are responsible for the development of bAVM. Our previous work identified the presence of somatic activating KRAS mutations in endothelial cells (ECs) isolated from clinical bAVM tissue. As such, we performed this proteomics study to profile the molecular impact of mutant KRAS expression on endothelial biology. We engineered a human EC model with doxycycline-inducible expression of mutant KRAS G12V. As mutant KRAS ECs preferentially activated the MAPK/ERK signaling cascade with no change to the activities of PI3K/AKT or MAPK/p38 pathways, we also included a MEK inhibitor (SL327) in this study to delineate MEK-dependent versus MEK-independent proteome changes.