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Peer-reviewedCC BY 4.0Communications Biology

Loss of endothelial ZEB1 enhances neovascularisation during choroidal neovascularisation

  • Nicholas Beazley-Long1,2
  • Joseph L. Horder1
  • Kathryn R. Green1
  • Joshua H. Bourne3,4
  • Amy P. Lynch1
  • Nada S. Ahmed1
  • Zarah B. Tabrizi1
  • Guillermo Diez-Pinel1
  • Christopher P. Carroll5
  • Claire L. Allen6
  • Charles T. Cresswell1
  • Poppy E. Harris1
12 more authors
  • Isabela Ferreira1
  • Diogo Mosqueira7
  • Julie Rayes3
  • Nigel P. Mongan8,9
  • John King10
  • Chris Denning7
  • Alan McIntyre5
  • Marc P. Stemmler11
  • Simone Brabletz11
  • Thomas Brabletz11
  • David O. Bates6
  • Andrew V. Benest1
11 affiliations
  1. 1Endothelial Quiescence Group COMPARE and Centre for Cancer Sciences School of Medicine, Biodiscovery Institute, University of Nottingham, Nottingham, UK
  2. 2Data Integrity and QA Team, Faculty of Health and Life Sciences, University of Bristol, Bristol, UK
  3. 3Institute of Cardiovascular Sciences, University of Birmingham, Edgbaston, Birmingham, UK
  4. 4Present Address: Centre for Inflammatory Diseases, Department of Medicine, School of Clinical Sciences, Monash Medical Centre, Monash University, Clayton, VIC Australia
  5. 5Hypoxia and Acidosis Group Centre for Cancer Sciences, School of Medicine, BioDiscovery Institute, University of Nottingham, Nottingham, UK
  6. 6Tumour Vascular Biology Group COMPARE and Centre for Cancer Sciences School of Medicine, Biodiscovery Institute, University of Nottingham, Nottingham, UK
  7. 7Stem Cell Biology Group COMPARE and Centre for Cancer Sciences, School of Medicine, Biodiscovery Institute, University of Nottingham, Nottingham, UK
  8. 8Biodiscovery Institute, School of Veterinary Medicine and Science, University of Nottingham, Nottingham, UK
  9. 9Department of Pharmacology, Weill Cornell Medicine, New York, NY USA
  10. 10School of Mathematical Sciences, University of Nottingham, Nottingham, UK
  11. 11Friederich-Alexander-Univerisity Erlangen, Department of Experimental Medicine 1, Nikolaus-Fiebiger Center for Molecular Medicine, Erlangen, Germany
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Abstract

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.

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Cite

BibTeXRIS
BibTeX
@article{beazleylong2026loss,
  title = {{Loss of endothelial ZEB1 enhances neovascularisation during choroidal neovascularisation}},
  author = {Nicholas Beazley-Long and Joseph L. Horder and Kathryn R. Green and Joshua H. Bourne and Amy P. Lynch and Nada S. Ahmed and Zarah B. Tabrizi and Guillermo Diez-Pinel and Christopher P. Carroll and Claire L. Allen and Charles T. Cresswell and Poppy E. Harris and Isabela Ferreira and Diogo Mosqueira and Julie Rayes and Nigel P. Mongan and John King and Chris Denning and Alan McIntyre and Marc P. Stemmler and Simone Brabletz and Thomas Brabletz and David O. Bates and Andrew V. Benest},
  journal = {Communications Biology},
  year = {2026},
  month = jul,
  doi = {10.1038/s42003-026-10630-0},
  url = {https://doi.org/10.1038/s42003-026-10630-0},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - Loss of endothelial ZEB1 enhances neovascularisation during choroidal neovascularisation
AU  - Nicholas Beazley-Long
AU  - Joseph L. Horder
AU  - Kathryn R. Green
AU  - Joshua H. Bourne
AU  - Amy P. Lynch
AU  - Nada S. Ahmed
AU  - Zarah B. Tabrizi
AU  - Guillermo Diez-Pinel
AU  - Christopher P. Carroll
AU  - Claire L. Allen
AU  - Charles T. Cresswell
AU  - Poppy E. Harris
AU  - Isabela Ferreira
AU  - Diogo Mosqueira
AU  - Julie Rayes
AU  - Nigel P. Mongan
AU  - John King
AU  - Chris Denning
AU  - Alan McIntyre
AU  - Marc P. Stemmler
AU  - Simone Brabletz
AU  - Thomas Brabletz
AU  - David O. Bates
AU  - Andrew V. Benest
PY  - 2026
DA  - 2026/07/07
JO  - Communications Biology
DO  - 10.1038/s42003-026-10630-0
UR  - https://doi.org/10.1038/s42003-026-10630-0
AB  - 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.
SN  - 2399-3642
ER  -