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<p>GTP binding protein 3 (GTPBP3) is a highly conserved enzyme involved in tRNA modification, is essential for 5-taurinomethyluridine (τm<sup>5</sup>U) biosynthesis, and is linked to mitochondrial dysfunction within cells. However, the specific roles of GTPBP3 in different cell types during vascular development and angiogenesis are not well understood. In this study, we assess the physiological functions of GTPBP3 in endothelial cells (ECs) using two conditional knockout mouse models. GTPBP3 deletion, specifically in ECs, resulted in embryonic lethality owing to irregularities in angiogenesis and vascular formation. Tamoxifen-inducible EC-specific GTPBP3 knockout (<i>Gtpbp3</i><sup><i>iΔEC</i></sup>) mice show reduced retinal sprouting angiogenesis and impaired neovascularization after limb ischemia. Mechanistically, GTPBP3 absence in ECs leads to mitochondrial dysfunction and an increase in mitochondrial reactive oxygen species (mtROS), which alters Heme-regulated eIF2α kinase (HRI)—activating transcription factor 4 (ATF4)—Sestrin2 pathway expression, inhibiting activation of the mTORC1 pathway and angiogenesis. However, treatment with MitoQ—an mtROS scavenger—improves angiogenic dysfunction. These results highlight GTPBP3 as a vital element for developmental angiogenesis and neovascularization after limb ischemia.</p>

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Endothelial GTPBP3 directs developmental angiogenesis and neovascularization after limb ischemia via the mtROS/HRl/ATF4/mTORC1 axis

  • 期刊论文

  • 发表日期：

    2025年6月18日

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  • Donglu Qin,
  • Jiarui Hu,
  • Yang Yang,
  • Xin Li,
  • Jia He,
  • Jin Chen,
  • Xin Guo,
  • Cheng Wei,
  • Fengjiao Wang,
  • Ting Yi,
  • Chenyu Li,
  • Bilian Yu

摘要

GTP binding protein 3 (GTPBP3) is a highly conserved enzyme involved in tRNA modification, is essential for 5-taurinomethyluridine (τm5U) biosynthesis, and is linked to mitochondrial dysfunction within cells. However, the specific roles of GTPBP3 in different cell types during vascular development and angiogenesis are not well understood. In this study, we assess the physiological functions of GTPBP3 in endothelial cells (ECs) using two conditional knockout mouse models. GTPBP3 deletion, specifically in ECs, resulted in embryonic lethality owing to irregularities in angiogenesis and vascular formation. Tamoxifen-inducible EC-specific GTPBP3 knockout (Gtpbp3iΔEC) mice show reduced retinal sprouting angiogenesis and impaired neovascularization after limb ischemia. Mechanistically, GTPBP3 absence in ECs leads to mitochondrial dysfunction and an increase in mitochondrial reactive oxygen species (mtROS), which alters Heme-regulated eIF2α kinase (HRI)—activating transcription factor 4 (ATF4)—Sestrin2 pathway expression, inhibiting activation of the mTORC1 pathway and angiogenesis. However, treatment with MitoQ—an mtROS scavenger—improves angiogenic dysfunction. These results highlight GTPBP3 as a vital element for developmental angiogenesis and neovascularization after limb ischemia.