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<p>The restoration of the microvasculature is essential to cardiovascular regeneration. Our previous work demonstrated that angiogenic transdifferentiation of fibroblasts into endothelial cells facilitates vascular recovery following limb ischemia and is accompanied by a metabolic shift toward glycolysis. However, a comprehensive characterization of the metabolic alterations that contribute to the transdifferentiation process is still lacking. Here we identify a marked upregulation of uridine diphosphate <i>N</i>-acetylglucosamine (UDP-GlcNAc), the substrate for <i>O</i>-GlcNAcylation, during transdifferentiation. Enhancing this pathway promotes, whereas inhibiting it impairs, the efficiency of transdifferentiation. Mechanistically, we demonstrate that <i>O</i>-GlcNAcylation facilitates chromatin remodeling through modification of HIRA, a histone chaperone responsible for de novo deposition of the noncanonical histone variant H3.3, a process intimately linked to transcriptional activation. These findings are further supported by in vivo lineage tracing and conditional knockout mouse models. Collectively, our study demonstrates that <i>O</i>-GlcNAcylation enhances angiogenic transdifferentiation through a metabolic-and-epigenetic-coupled mechanism, thereby strengthening vascular recovery.</p>

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O-GlcNAcylation promotes angiogenic transdifferentiation to reverse vascular ischemia

  • 期刊论文

  • 发表日期：

    2025年7月4日

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  • Shuang Li,
  • Alexander J. Lu,
  • Eric S. Nagueh,
  • Yanqiang Li,
  • Michael Graber,
  • Kaylee N. Carter,
  • Elisa Morales,
  • Crystina L. Kriss,
  • Kaifu Chen,
  • Junchen Liu,
  • Guangyu Wang,
  • John P. Cooke,
  • Li Lai

摘要

The restoration of the microvasculature is essential to cardiovascular regeneration. Our previous work demonstrated that angiogenic transdifferentiation of fibroblasts into endothelial cells facilitates vascular recovery following limb ischemia and is accompanied by a metabolic shift toward glycolysis. However, a comprehensive characterization of the metabolic alterations that contribute to the transdifferentiation process is still lacking. Here we identify a marked upregulation of uridine diphosphate N-acetylglucosamine (UDP-GlcNAc), the substrate for O-GlcNAcylation, during transdifferentiation. Enhancing this pathway promotes, whereas inhibiting it impairs, the efficiency of transdifferentiation. Mechanistically, we demonstrate that O-GlcNAcylation facilitates chromatin remodeling through modification of HIRA, a histone chaperone responsible for de novo deposition of the noncanonical histone variant H3.3, a process intimately linked to transcriptional activation. These findings are further supported by in vivo lineage tracing and conditional knockout mouse models. Collectively, our study demonstrates that O-GlcNAcylation enhances angiogenic transdifferentiation through a metabolic-and-epigenetic-coupled mechanism, thereby strengthening vascular recovery.