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Endothelial protein C receptor promotes retinal neovascularization through heme catabolism

Author

Listed:
  • Hongyuan Song

    (Shanghai Changhai Hospital
    Shanghai Jiao Tong University School of Medicine
    National Clinical Research Center for Ophthalmic Diseases
    University of Shanghai for Science and Technology)

  • Qing Li

    (Shanghai Changhai Hospital
    The Affiliated Eye Hospital of Nanjing Medical University)

  • Xiao Gui

    (Shanghai Changhai Hospital
    Yuanwang Hospital)

  • Ziyu Fang

    (Shanghai Changhai Hospital)

  • Wen Zhou

    (Shanghai Changhai Hospital)

  • Mengzhu Wang

    (Shanghai Changhai Hospital)

  • Yuxin Jiang

    (Shanghai Jiao Tong University School of Medicine
    Shanghai Key Laboratory of Fundus Diseases)

  • Ajun Geng

    (Hangzhou Institute for Advanced Study
    University of Chinese Academy of Sciences)

  • Xi Shen

    (Shanghai Jiao Tong University School of Medicine)

  • Yongxuan Liu

    (Shanghai Changhai Hospital)

  • Haorui Zhang

    (Shanghai Changhai Hospital)

  • Zheng Nie

    (Shanghai Changhai Hospital)

  • Lin Zhang

    (Shanghai Changhai Hospital)

  • Huimin Zhu

    (Shanghai Changhai Hospital)

  • Feng Zhang

    (Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science)

  • Xuri Li

    (Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science)

  • Fanyan Luo

    (Central South University)

  • Hongjian Zhang

    (University of Shanghai for Science and Technology
    999 Shiguang Road)

  • Wei Shen

    (Shanghai Changhai Hospital)

  • Xiaodong Sun

    (Shanghai Jiao Tong University School of Medicine
    National Clinical Research Center for Ophthalmic Diseases
    Shanghai Key Laboratory of Fundus Diseases)

Abstract

Pathological retinal neovascularization (RNV) is one of the leading causes of blindness worldwide; however, its underlying mechanism remains unclear. Here, we found that the expression of endothelial protein C receptor (Epcr) was increased during RNV, and its ligand was elevated in the serum or vitreous body of patients with proliferative diabetic retinopathy. Deleting endothelial Epcr or using an EPCR-neutralizing antibody ameliorated pathological retinal angiogenesis. EPCR promoted endothelial heme catabolism and carbon monoxide release through heme oxygenase 1 (HO-1). Inhibition of heme catabolism by deleting endothelial Ho-1 or using an HO-1 inhibitor suppressed pathological angiogenesis in retinopathy. Conversely, supplementation with carbon monoxide rescued the angiogenic defects after endothelial Epcr or Ho-1 deletion. Our results identified EPCR-dependent endothelial heme catabolism as an important contributor to pathological angiogenesis, which may serve as a potential target for treating vasoproliferative retinopathy.

Suggested Citation

  • Hongyuan Song & Qing Li & Xiao Gui & Ziyu Fang & Wen Zhou & Mengzhu Wang & Yuxin Jiang & Ajun Geng & Xi Shen & Yongxuan Liu & Haorui Zhang & Zheng Nie & Lin Zhang & Huimin Zhu & Feng Zhang & Xuri Li &, 2025. "Endothelial protein C receptor promotes retinal neovascularization through heme catabolism," Nature Communications, Nature, vol. 16(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-56810-0
    DOI: 10.1038/s41467-025-56810-0
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