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<p>Angiogenesis is essential for development and tissue repair after ischemia. Reactive oxygen species (ROS) act as signaling molecules that promote angiogenesis in endothelial cells (ECs) which mainly rely on aerobic glycolysis for energy production. However, how redox signaling couples to endothelial metabolism remains unclear. Here, we identify endothelial Drp1 as a redox sensor that links VEGF-induced H₂O₂ signaling to metabolic reprogramming and angiogenesis. Loss of Drp1 in ECs suppresses VEGF-driven angiogenic responses. Mechanistically, VEGF rapidly induces NOX4-dependent sulfenylation of Drp1 at Cys<sup>644</sup>, promoting disulfide bond with the metabolic kinase AMPK and subsequent oxidation of AMPK at Cys<sup>299/304</sup> via mitochondrial fission-derived ROS. This pathway enhances endothelial glycolysis and angiogenesis. In vivo, mice with endothelial Drp1 deficiency or CRISPR-engineered redox-dead Drp1 (Cys to Ala) knock-in exhibit impaired retinal angiogenesis and post-ischemic neovascularization. Thus, endothelial Drp1 integrates mitochondrial redox signaling with glycolysis through cysteine oxidation-mediated Drp1-AMPK redox relay, thereby driving reparative neovascularization.</p>

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Endothelial Drp1 integrates VEGF-induced redox signaling with glycolysis through cysteine oxidation to drive angiogenesis

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月20日

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  • Sheela Nagarkoti,
  • Young-Mee Kim,
  • Archita Das,
  • Dipankar Ash,
  • Eric A. Vitriol,
  • Tracy-Ann Read,
  • Varadarajan Sudhahar,
  • Md. Selim Hossain,
  • Shikha Yadav,
  • Stephanie Kelley Spears,
  • Kelvin N. Orji,
  • Maritza J. Romero,
  • Rudolf Lucas,
  • David Stepp,
  • Eric J. Belin de Chantemele,
  • Ruth B. Caldwell,
  • David JR. Fulton,
  • Tohru Fukai,
  • Masuko Ushio-Fukai

摘要

Angiogenesis is essential for development and tissue repair after ischemia. Reactive oxygen species (ROS) act as signaling molecules that promote angiogenesis in endothelial cells (ECs) which mainly rely on aerobic glycolysis for energy production. However, how redox signaling couples to endothelial metabolism remains unclear. Here, we identify endothelial Drp1 as a redox sensor that links VEGF-induced H₂O₂ signaling to metabolic reprogramming and angiogenesis. Loss of Drp1 in ECs suppresses VEGF-driven angiogenic responses. Mechanistically, VEGF rapidly induces NOX4-dependent sulfenylation of Drp1 at Cys644, promoting disulfide bond with the metabolic kinase AMPK and subsequent oxidation of AMPK at Cys299/304 via mitochondrial fission-derived ROS. This pathway enhances endothelial glycolysis and angiogenesis. In vivo, mice with endothelial Drp1 deficiency or CRISPR-engineered redox-dead Drp1 (Cys to Ala) knock-in exhibit impaired retinal angiogenesis and post-ischemic neovascularization. Thus, endothelial Drp1 integrates mitochondrial redox signaling with glycolysis through cysteine oxidation-mediated Drp1-AMPK redox relay, thereby driving reparative neovascularization.