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

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 Cys^299/304 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.