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Background <p>Ocular neovascularization is a leading cause of blindness. Hypoxia is associated with retinal angiogenesis. Hypoxia results in lactate accumulation, which typically precedes protein lactylation, and this plays a crucial role in ocular neovascularization. However, the underlying mechanism remains unclear. Here, we investigate the role of the DNA methyltransferase, DNMT3A, in regulating lactylation following hypoxia in ocular neovascularization.</p> Results <p>DNMT3A controls endothelial cell angiogenesis via regulating lactate-derived HIF-1α lactylation. During oxygen-induced retinopathy progression, we detected increased levels of DNMT3A, HIF-1α lactylation, and vascular endothelial growth factor (VEGF) in endothelial cells. Exogenous lactate administration significantly enhances vascularization, while inhibiting lactate uptake in the presence or absence of DNMT3A prevents endothelial cell angiogenesis and attenuates HIF-1α lactylation. We demonstrate that modulating DNMT3A expression alters HIF-1α lactylation levels, influencing angiogenesis in vitro and in vivo.</p> Conclusions <p>DNMT3A facilitates lactate transport into the nucleus, where it promotes VEGFA upregulation through HIF-1α lactylation, thereby stimulating endothelial cell angiogenesis. Targeting the lactate-DNMT3A/HIF-1α lactylation/VEGFA pathway could provide new therapeutic strategies for treating ocular neovascularization disorders.</p>

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Lactate-binding protein DNMT3A in HRMECs promotes angiogenesis by upregulating VEGFA through HIF-1α lactylation

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年10月30日

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  • Xiaotang Wang,
  • Jiaxing Huang,
  • Wei Fan,
  • Na Li,
  • Hui Yang,
  • Wenxian Yang,
  • Wanqian Li,
  • Ruonan Li,
  • Jiangyi Liu,
  • Xingran Li,
  • Qian Zhou,
  • Shengping Hou

摘要

Background

Ocular neovascularization is a leading cause of blindness. Hypoxia is associated with retinal angiogenesis. Hypoxia results in lactate accumulation, which typically precedes protein lactylation, and this plays a crucial role in ocular neovascularization. However, the underlying mechanism remains unclear. Here, we investigate the role of the DNA methyltransferase, DNMT3A, in regulating lactylation following hypoxia in ocular neovascularization.

Results

DNMT3A controls endothelial cell angiogenesis via regulating lactate-derived HIF-1α lactylation. During oxygen-induced retinopathy progression, we detected increased levels of DNMT3A, HIF-1α lactylation, and vascular endothelial growth factor (VEGF) in endothelial cells. Exogenous lactate administration significantly enhances vascularization, while inhibiting lactate uptake in the presence or absence of DNMT3A prevents endothelial cell angiogenesis and attenuates HIF-1α lactylation. We demonstrate that modulating DNMT3A expression alters HIF-1α lactylation levels, influencing angiogenesis in vitro and in vivo.

Conclusions

DNMT3A facilitates lactate transport into the nucleus, where it promotes VEGFA upregulation through HIF-1α lactylation, thereby stimulating endothelial cell angiogenesis. Targeting the lactate-DNMT3A/HIF-1α lactylation/VEGFA pathway could provide new therapeutic strategies for treating ocular neovascularization disorders.