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

Angiogenesis. 2025 Jun 18;28(3):36. doi: 10.1007/s10456-025-09994-4.

Abstract

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.

Keywords: Angiogenesis; GTP binding protein 3; Mitochondrial function; MtROS; mTORC1.

MeSH terms

  • Activating Transcription Factor 4* / genetics
  • Activating Transcription Factor 4* / metabolism
  • Angiogenesis
  • Animals
  • Endothelial Cells* / metabolism
  • Endothelial Cells* / pathology
  • Extremities* / blood supply
  • Hindlimb* / blood supply
  • Ischemia* / genetics
  • Ischemia* / metabolism
  • Ischemia* / pathology
  • Mechanistic Target of Rapamycin Complex 1* / metabolism
  • Mice
  • Mice, Knockout
  • Mitochondria / metabolism
  • Monomeric GTP-Binding Proteins* / genetics
  • Monomeric GTP-Binding Proteins* / metabolism
  • Neovascularization, Physiologic*
  • Reactive Oxygen Species* / metabolism
  • Signal Transduction

Substances

  • Mechanistic Target of Rapamycin Complex 1
  • Activating Transcription Factor 4
  • Reactive Oxygen Species
  • Atf4 protein, mouse
  • Monomeric GTP-Binding Proteins