Metabolic Reprogramming of Endothelial Cells with KRAS Mutations in the Pathobiology of Sporadic Brain Arteriovenous Malformations
Year: 2026
Type: dissertation
Abstract: Brain arteriovenous malformation (bAVM) is a disease characterized by the formation of tangled blood vessels with direct connections between arteries and veins. It often develops early in life and causes devastating health impacts to patients, such as hemorrhagic stroke. Treatment for bAVM relies solely on surgical interventions, which are not suitable for all patients due to excessive risks. There is currently no approved pharmacological therapy for bAVM, largely due to our insufficient understanding of the underlying molecular mechanisms driving the pathogenesis of this disease. Our previous work identified the presence of somatic activating KRAS mutations (p.G12D, p.G12V, p.Q61H) in endothelial cells (ECs) isolated from clinical bAVM tissue. Subsequent animal studies showed that EC-specific expression of mutant KRAS was sufficient to induce pathological vascular remodeling, resembling clinical bAVM phenotypes, including the formation of enlarged and tangled blood vessels. KRAS mutations are also well-known oncogenic mutations, and one distinguishing feature of cancer cells is their augmented glucose metabolism, also known as the Warburg Effect. Given that enhanced glycolysis has been implicated in EC angiogenesis, I aim to investigate if the Warburg Effect is also involved in the pathogenesis of bAVM to drive abnormal vascular remodeling. As such, I engineered a human EC model with inducible expression of mutant KRASG12V. I observed a significant increase in EC glycolysis and angiogenesis upon mutant KRAS expression. Mechanistically, I found that this metabolic shift was facilitated by enhanced membrane localization of glucose transporters (e.g., GLUT1) and MEK-dependent induction of hexokinase-2 (HK2) expression. Importantly, RNA-sequencing and proteomics revealed that HK2 appeared to be the only glycolytic component elevated in KRASG12V ECs and that this glycolytic signature in bAVM was distinct from brain tumor ECs, based on single-cell RNA-sequencing datasets. Furthermore, pharmacologic inhibition of glycolytic flux or siRNA knockdown of HK2 suppressed sprouting angiogenesis and restored other pathological changes in KRASG12V ECs. Arteriovenous shunts were also reversed by MEK and/or glycolysis inhibition in a KRAS-mutant zebrafish model. Finally, glycolysis inhibition potentiated the effect of MEK inhibition on angiogenesis in patient-derived bAVM primary ECs. Together, this project demonstrated that KRAS-driven reprogramming of endothelial metabolism represents a rational therapeutic target in bAVMs.
Source: TSpace (University of Toronto)
Author: Wu, Ruilin
Institution: University of Toronto
Language: English
Subfield: Neurology
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W7203956941