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<p>Retinal angiogenesis drives both normal vascular development and sight-threatening retinal vascular diseases. While mitochondria are known to fuel this process, the roles of many specific mitochondrial proteins are poorly understood. Here we show that the mitochondrial protein RAB5 interacting factor (RAB5IF) as a critical pro-angiogenic regulator of physiological retinal vascular development in neonatal mice (sex-balanced) and pathological retinal angiogenesis in two models: oxygen-induced retinopathy mice (sex-balanced) and laser-induced choroidal neovascularization mice (sex-balanced). Proteomic sequencing identified SUMO2 as a critical downstream protein of RAB5IF. RAB5IF silencing impeded mitochondrial respiration and ribosome biogenesis, specifically suppressing <i>SUMO2</i> mRNA translation initiation and consequently lowering SUMO2 protein levels in retinal microvascular endothelial cells. We also identify that SUMO2-mediated SUMOylation of Gαi1/3 is required for their roles in mediating VEGF signaling. Mutations at the SUMOylation sites of Gαi1/3 hindered VEGF-induced signaling and pro-angiogenic activity. Together, these findings delineate a RAB5IF-SUMO2-Gαi1/3 signaling axis essential for retinal angiogenesis, presenting new therapeutic targets for neovascular eye diseases.</p>

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Endothelial RAB5IF is required for pathological and developmental retinal angiogenesis

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年12月13日

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  • Wen Bai,
  • De-pei Yin,
  • Gang Chen,
  • Yao Lu,
  • Qin Jiang,
  • Ke-ran Li,
  • Jin Yao,
  • Cong Cao

摘要

Retinal angiogenesis drives both normal vascular development and sight-threatening retinal vascular diseases. While mitochondria are known to fuel this process, the roles of many specific mitochondrial proteins are poorly understood. Here we show that the mitochondrial protein RAB5 interacting factor (RAB5IF) as a critical pro-angiogenic regulator of physiological retinal vascular development in neonatal mice (sex-balanced) and pathological retinal angiogenesis in two models: oxygen-induced retinopathy mice (sex-balanced) and laser-induced choroidal neovascularization mice (sex-balanced). Proteomic sequencing identified SUMO2 as a critical downstream protein of RAB5IF. RAB5IF silencing impeded mitochondrial respiration and ribosome biogenesis, specifically suppressing SUMO2 mRNA translation initiation and consequently lowering SUMO2 protein levels in retinal microvascular endothelial cells. We also identify that SUMO2-mediated SUMOylation of Gαi1/3 is required for their roles in mediating VEGF signaling. Mutations at the SUMOylation sites of Gαi1/3 hindered VEGF-induced signaling and pro-angiogenic activity. Together, these findings delineate a RAB5IF-SUMO2-Gαi1/3 signaling axis essential for retinal angiogenesis, presenting new therapeutic targets for neovascular eye diseases.