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Peer-reviewedCC BY 4.0iMeta

Dissecting the angiogenic mechanism of pachychoroid polypoidal choroidal vasculopathy

  • Xinyu Zhao1,2,3
  • Tiantian Cheng4
  • Wenfei Zhang1,2,3
  • Xingwang Gu1,2,3
  • Qing Zhao1,2,3
  • Yaning Chen5,6
  • Lihui Meng1,2,3
  • Jiaqi Zhang1,2,3
  • Bintao Qiu7
  • Lili Li8
  • Shiyu Cheng1,2,3
  • Zicheng Wang5,6
7 more authors
  • Chuting Wang1,2,3
  • Yuelin Wang9
  • Zuyi Yang1,2,3
  • Zhengming Shi1,2,3
  • Ye Guo10
  • Shengzhi Liu5,6
  • Youxin Chen1,2,3
10 affiliations
  1. 1Department of Ophthalmology Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College Beijing China
  2. 2Beijing Key Laboratory of Fundus Diseases Intelligent Diagnosis & Drug/Device Development and Translation Beijing China
  3. 3Key Laboratory of Ocular Fundus Diseases, Chinese Academy of Medical Sciences Beijing China
  4. 4Department of Ophthalmology, the First Affiliated Hospital, School of Medicine Zhejiang University Hangzhou Zhejiang China
  5. 5School of Pharmaceutical Sciences Capital Medical University Beijing China
  6. 6Beijing Area Major Laboratory of Peptide and Small Molecular Drugs Capital Medical University Beijing China
  7. 7Institute of Clinical Medicine National Infrastructure for Translational Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College Beijing China
  8. 8State Key Laboratory of Common Mechanism Research of Major Diseases, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences and Peking Union Medical College Beijing China
  9. 9Department of Ophthalmology Peking University Third Hospital Beijing China
  10. 10Department of Clinical Laboratory State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College Beijing China
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Abstract

Polypoidal choroidal vasculopathy (PCV) is a distinct variant of neovascular age‐related macular degeneration (AMD) and a major cause of vision loss in older adults, yet its pathogenesis remains poorly understood. Pachychoroid PCV is a subtype characterized by poor treatment response, minimal typical AMD features, and dilated choroidal vessels. Using a multicenter PCV cohort, we conducted plasma multi‐omics analyses and identified enrichment of fluid shear stress and atherosclerosis (FSS‐AS) signaling pathways in this subtype. The pachychoroid phenotype, together with FSS‐AS enrichment, implicated altered choroidal hemodynamics in its pathogenesis. By inducing choroidal circulatory hypertension (CCH) in mice, we recapitulated, for the first time, the hallmark ocular lesions of pachychoroid PCV. Single‐cell sequencing identified the cellular origin of these angiogenic lesions and implicated endothelin‐1 (EDN1) as a key effector. Alleviating choroidal hypertension, reducing EDN1 expression, or pharmacologically blocking the endothelin receptor A (EDNRA, the receptor for EDN1), prevented lesion formation. In vitro, disturbed fluid shear stress upregulated EDN1 in choroidal endothelial cells and promoted pathological remodeling and angiogenesis through EDNRA. Collectively, our findings define a pathogenic cascade wherein CCH induces abnormal hemodynamics (disrupted fluid shear stress) and drives angiogenesis via the EDN1/EDNRA axis, offering mechanistic insight and identifying a potential therapeutic target for pachychoroid PCV.

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Cite

BibTeXRIS
BibTeX
@article{zhao2026dissecting,
  title = {{Dissecting the angiogenic mechanism of pachychoroid polypoidal choroidal vasculopathy}},
  author = {Xinyu Zhao and Tiantian Cheng and Wenfei Zhang and Xingwang Gu and Qing Zhao and Yaning Chen and Lihui Meng and Jiaqi Zhang and Bintao Qiu and Lili Li and Shiyu Cheng and Zicheng Wang and Chuting Wang and Yuelin Wang and Zuyi Yang and Zhengming Shi and Ye Guo and Shengzhi Liu and Youxin Chen},
  journal = {iMeta},
  year = {2026},
  month = sep,
  doi = {10.1002/imt2.70176},
  url = {https://doi.org/10.1002/imt2.70176},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - Dissecting the angiogenic mechanism of pachychoroid polypoidal choroidal vasculopathy
AU  - Xinyu Zhao
AU  - Tiantian Cheng
AU  - Wenfei Zhang
AU  - Xingwang Gu
AU  - Qing Zhao
AU  - Yaning Chen
AU  - Lihui Meng
AU  - Jiaqi Zhang
AU  - Bintao Qiu
AU  - Lili Li
AU  - Shiyu Cheng
AU  - Zicheng Wang
AU  - Chuting Wang
AU  - Yuelin Wang
AU  - Zuyi Yang
AU  - Zhengming Shi
AU  - Ye Guo
AU  - Shengzhi Liu
AU  - Youxin Chen
PY  - 2026
DA  - 2026/09/30
JO  - iMeta
DO  - 10.1002/imt2.70176
UR  - https://doi.org/10.1002/imt2.70176
AB  - Polypoidal choroidal vasculopathy (PCV) is a distinct variant of neovascular age‐related macular degeneration (AMD) and a major cause of vision loss in older adults, yet its pathogenesis remains poorly understood. Pachychoroid PCV is a subtype characterized by poor treatment response, minimal typical AMD features, and dilated choroidal vessels. Using a multicenter PCV cohort, we conducted plasma multi‐omics analyses and identified enrichment of fluid shear stress and atherosclerosis (FSS‐AS) signaling pathways in this subtype. The pachychoroid phenotype, together with FSS‐AS enrichment, implicated altered choroidal hemodynamics in its pathogenesis. By inducing choroidal circulatory hypertension (CCH) in mice, we recapitulated, for the first time, the hallmark ocular lesions of pachychoroid PCV. Single‐cell sequencing identified the cellular origin of these angiogenic lesions and implicated endothelin‐1 (EDN1) as a key effector. Alleviating choroidal hypertension, reducing EDN1 expression, or pharmacologically blocking the endothelin receptor A (EDNRA, the receptor for EDN1), prevented lesion formation. In vitro, disturbed fluid shear stress upregulated EDN1 in choroidal endothelial cells and promoted pathological remodeling and angiogenesis through EDNRA. Collectively, our findings define a pathogenic cascade wherein CCH induces abnormal hemodynamics (disrupted fluid shear stress) and drives angiogenesis via the EDN1/EDNRA axis, offering mechanistic insight and identifying a potential therapeutic target for pachychoroid PCV.
SN  - 2770-5986
SN  - 2770-596X
ER  -