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<p>Choroidal neovascularisation (CNV) is a hallmark of wet/neovascular age-related macular degeneration (wAMD), characterized by aberrant blood vessel growth from the choroid into the retina. Both pathological angiogenesis and inflammation contribute to disease progression. Here we show that analsysis of single-cell RNA sequencing of experimental CNV lesions revealed upregulation of <i>Zeb1</i> in angiogenic endothelial cells (ECs). We generated an endothelial-specific <i>Zeb1</i> knockout (<i>Zeb1</i><sup>iECKO</sup>) mouse model to assess its functional role. CNV was induced via laser photocoagulation, and vascular leakage and inflammation were evaluated using fluorescein angiography, immunohistochemistry, and transcriptomic analyses. <i>Zeb1</i><sup>iECKO</sup> mice exhibited increased fluorescein leakage and enhanced vascular invasion during CNV, indicating destabilized neovascular structures. However, leukocyte infiltration within CNV lesions was not elevated. In vitro, <i>ZEB1</i> knockdown in human ECs led to downregulation of inflammatory signalling pathways and reduced expression of adhesion molecules in response to TNF-α stimulation yet retained angiogenic capacity. ZEB1 coordinates angiogenic and inflammatory responses in CNV. Its loss enhances neovascularisation without promoting inflammation, suggesting a potential therapeutic target for modulating pathological angiogenesis in wAMD while minimizing inflammatory damage.</p>

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Loss of endothelial ZEB1 enhances neovascularisation during choroidal neovascularisation

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年7月7日

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  • Nicholas Beazley-Long,
  • Joseph L. Horder,
  • Kathryn R. Green,
  • Joshua H. Bourne,
  • Amy P. Lynch,
  • Nada S. Ahmed,
  • Zarah B. Tabrizi,
  • Guillermo Diez-Pinel,
  • Christopher P. Carroll,
  • Claire L. Allen,
  • Charles T. Cresswell,
  • Poppy E. Harris,
  • Isabela Ferreira,
  • Diogo Mosqueira,
  • Julie Rayes,
  • Nigel P. Mongan,
  • John King,
  • Chris Denning,
  • Alan McIntyre,
  • Marc P. Stemmler,
  • Simone Brabletz,
  • Thomas Brabletz,
  • David O. Bates,
  • Andrew V. Benest

摘要

Choroidal neovascularisation (CNV) is a hallmark of wet/neovascular age-related macular degeneration (wAMD), characterized by aberrant blood vessel growth from the choroid into the retina. Both pathological angiogenesis and inflammation contribute to disease progression. Here we show that analsysis of single-cell RNA sequencing of experimental CNV lesions revealed upregulation of Zeb1 in angiogenic endothelial cells (ECs). We generated an endothelial-specific Zeb1 knockout (Zeb1iECKO) mouse model to assess its functional role. CNV was induced via laser photocoagulation, and vascular leakage and inflammation were evaluated using fluorescein angiography, immunohistochemistry, and transcriptomic analyses. Zeb1iECKO mice exhibited increased fluorescein leakage and enhanced vascular invasion during CNV, indicating destabilized neovascular structures. However, leukocyte infiltration within CNV lesions was not elevated. In vitro, ZEB1 knockdown in human ECs led to downregulation of inflammatory signalling pathways and reduced expression of adhesion molecules in response to TNF-α stimulation yet retained angiogenic capacity. ZEB1 coordinates angiogenic and inflammatory responses in CNV. Its loss enhances neovascularisation without promoting inflammation, suggesting a potential therapeutic target for modulating pathological angiogenesis in wAMD while minimizing inflammatory damage.