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<p>Somatic activating <i>KRAS</i> mutations in endothelial cells are the predominant cause of sporadic brain arteriovenous malformations (bAVMs) and also occur in sporadic extracranial AVMs. We found that KRAS<sup>G12V</sup> expression in the endothelium increased angiogenesis, which was accompanied by enhanced glucose uptake and glycolytic flux. Mechanistically, this increase in glycolysis was facilitated by enhanced membrane localization of glucose transporters (e.g., GLUT1) and induction of hexokinase-2 (HK2) expression. Importantly, RNA-sequencing and proteomics revealed that HK2 appeared to be the only glycolytic component elevated. Analysis of single-cell RNA-sequencing data and immunofluorescence staining confirmed that HK2 was elevated in mouse and human bAVMs. Critically, either pharmacologic inhibition of glycolytic flux or knockdown of <i>HK2</i> suppressed sprouting angiogenesis in cultured KRAS<sup>G12V</sup> endothelial cells. Glycolysis inhibition also reversed arteriovenous shunts and potentiated the effect of MEK inhibition in a KRAS-mutant zebrafish model. Finally, combined glycolysis and MEK inhibition suppressed angiogenesis in patient-derived bAVM primary endothelial cells. Together, our findings show that KRAS-driven reprogramming of endothelial metabolism represents a potential therapeutic vulnerability for sporadic AVMs.</p>

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KRAS-dependent glycolytic reprogramming of endothelial cells in sporadic arteriovenous malformations

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年2月18日

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  • Ruilin Wu,
  • Negar Khosraviani,
  • Ann Mansur,
  • Emilie Boudreau,
  • Gabrielle E Largoza,
  • Suejean Park,
  • Dakota Gustafson,
  • Sneha Raju,
  • Crizza Ching,
  • Amira Klip,
  • Thomas Wälchli,
  • Kathryn L Howe,
  • Ivan Radovanovic,
  • Joshua D Wythe,
  • Jason E Fish

摘要

Somatic activating KRAS mutations in endothelial cells are the predominant cause of sporadic brain arteriovenous malformations (bAVMs) and also occur in sporadic extracranial AVMs. We found that KRASG12V expression in the endothelium increased angiogenesis, which was accompanied by enhanced glucose uptake and glycolytic flux. Mechanistically, this increase in glycolysis was facilitated by enhanced membrane localization of glucose transporters (e.g., GLUT1) and induction of hexokinase-2 (HK2) expression. Importantly, RNA-sequencing and proteomics revealed that HK2 appeared to be the only glycolytic component elevated. Analysis of single-cell RNA-sequencing data and immunofluorescence staining confirmed that HK2 was elevated in mouse and human bAVMs. Critically, either pharmacologic inhibition of glycolytic flux or knockdown of HK2 suppressed sprouting angiogenesis in cultured KRASG12V endothelial cells. Glycolysis inhibition also reversed arteriovenous shunts and potentiated the effect of MEK inhibition in a KRAS-mutant zebrafish model. Finally, combined glycolysis and MEK inhibition suppressed angiogenesis in patient-derived bAVM primary endothelial cells. Together, our findings show that KRAS-driven reprogramming of endothelial metabolism represents a potential therapeutic vulnerability for sporadic AVMs.