KRAS-Dependent Metabolic Reprogramming of Endothelial Cells as a Therapeutic Vulnerability in Brain 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. Given the association between mutant KRAS, metabolic reprogramming and EC angiogenesis, we aimed to investigate if altered endothelial metabolism is involved in the pathogenesis of bAVM to drive abnormal vascular remodeling. As such, we engineered a human EC model with inducible expression of mutant KRAS G12V. We observed a significant increase in glucose metabolism upon mutant KRAS expression. This elevation in EC glycolysis contributes to the angiogenic behaviours that are observed in our mutant KRAS EC models. To further explore the transcriptional alterations underlying these changes, we performed this RNA-sequencing study with various glycolysis inhibitors and a MEK inhibitor (the major signaling pathway altered in mutant KRAS ECs) to profile the impact of glucose metabolism changes on endothelial biology.