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<p>Morphological changes in the ageing eye impede oxygen delivery from the choroid to the outer retina causing tissue hypoxia, which activates a molecular response that adapts the transcriptomic fingerprint of the retina and retinal pigment epithelium (RPE). This response, orchestrated by hypoxia-inducible transcription factors (HIFs), leads to the production of pro-angiogenic factors and plays a critical role in the development and pathogenesis of age-related macular degeneration (AMD). To evaluate the specific contribution of HIF1 to this response we expressed a constitutively active form of HIF1A in rod photoreceptors of the adult mouse retina. This elicited a transcriptional response characterized by the upregulation of genes involved in cell death, inflammation and angiogenesis, all of which play an important role in AMD. The HIF1-mediated response in rods caused severe retinal degeneration, disruption of the RPE and retinal neovascularization. Pathological vessels originated from the deep vascular plexus and penetrated the RPE resembling type 3 macular neovascularization observed in over 20% of patients with neovascular AMD. Our study provides further evidence for the involvement of tissue hypoxia in the pathogenesis of AMD and highlights the potential of HIF1A as a therapeutic target.</p>

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HIF1 activity in photoreceptors drives type 3 neovascularization and retinal atrophy in a new mouse model of age-related macular degeneration

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年10月6日

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  • Fredy Geiger,
  • Thomas Heigl,
  • Luca Merolla,
  • Marcus Yong,
  • Gabriele M. Wögenstein,
  • Larissa P. Govers,
  • Ioanna Tsioti,
  • Antonia Fottner,
  • Marijana Samardzija,
  • Christian Grimm

摘要

Morphological changes in the ageing eye impede oxygen delivery from the choroid to the outer retina causing tissue hypoxia, which activates a molecular response that adapts the transcriptomic fingerprint of the retina and retinal pigment epithelium (RPE). This response, orchestrated by hypoxia-inducible transcription factors (HIFs), leads to the production of pro-angiogenic factors and plays a critical role in the development and pathogenesis of age-related macular degeneration (AMD). To evaluate the specific contribution of HIF1 to this response we expressed a constitutively active form of HIF1A in rod photoreceptors of the adult mouse retina. This elicited a transcriptional response characterized by the upregulation of genes involved in cell death, inflammation and angiogenesis, all of which play an important role in AMD. The HIF1-mediated response in rods caused severe retinal degeneration, disruption of the RPE and retinal neovascularization. Pathological vessels originated from the deep vascular plexus and penetrated the RPE resembling type 3 macular neovascularization observed in over 20% of patients with neovascular AMD. Our study provides further evidence for the involvement of tissue hypoxia in the pathogenesis of AMD and highlights the potential of HIF1A as a therapeutic target.