Endothelial protein C receptor promotes retinal neovascularization through heme catabolism

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; Fanyan Luo; Hongjian Zhang; Wei Shen; Xiaodong Sun

doi:10.1038/s41467-025-56810-0

Endothelial protein C receptor promotes retinal neovascularization through heme catabolism

Nat Commun. 2025 Feb 13;16(1):1603. doi: 10.1038/s41467-025-56810-0.

Authors

Hongyuan Song^#^{1

2

3

4}, Qing Li^#^{5

6}, Xiao Gui^#^{5

7}, Ziyu Fang^#⁸, Wen Zhou^#⁵, Mengzhu Wang⁵, Yuxin Jiang^{9

10}, Ajun Geng^{11

12}, Xi Shen¹³, Yongxuan Liu⁵, Haorui Zhang⁵, Zheng Nie⁵, Lin Zhang⁵, Huimin Zhu⁵, Feng Zhang¹⁴, Xuri Li¹⁴, Fanyan Luo¹⁵, Hongjian Zhang^{16

17}, Wei Shen¹⁸, Xiaodong Sun^{19

20

21}

Affiliations

¹ Department of Ophthalmology, Shanghai Changhai Hospital, Shanghai, China. hongyuansong@hotmail.com.
² Department of Ophthalmology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. hongyuansong@hotmail.com.
³ National Clinical Research Center for Ophthalmic Diseases, Shanghai, China. hongyuansong@hotmail.com.
⁴ Oriental Pan-Vascular Devices Innovation College, University of Shanghai for Science and Technology, Shanghai, China. hongyuansong@hotmail.com.
⁵ Department of Ophthalmology, Shanghai Changhai Hospital, Shanghai, China.
⁶ The Affiliated Eye Hospital of Nanjing Medical University, Nanjing, China.
⁷ Department of Ophthalmology, Yuanwang Hospital, Wuxi, China.
⁸ Department of Urology, Shanghai Changhai Hospital, Shanghai, China.
⁹ Department of Ophthalmology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
¹⁰ Shanghai Key Laboratory of Fundus Diseases, Shanghai, China.
¹¹ Key Laboratory of Systems Health Science of Zhejiang Province, School of Life Science, Hangzhou Institute for Advanced Study, Hangzhou, China.
¹² New Cornerstone Science Laboratory, State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China.
¹³ Department of Ophthalmology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
¹⁴ State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou, China.
¹⁵ Department of Cardiac Surgery, Xiangya Hospital, Central South University, Changsha, China. drlfy@csu.edu.cn.
¹⁶ Oriental Pan-Vascular Devices Innovation College, University of Shanghai for Science and Technology, Shanghai, China. hongjian_zhang@usst.edu.cn.
¹⁷ Shidong Hospital Affiliated to University of Shanghai for Science and Technology, 999 Shiguang Road, Shanghai, China. hongjian_zhang@usst.edu.cn.
¹⁸ Department of Ophthalmology, Shanghai Changhai Hospital, Shanghai, China. shenwei@smmu.edu.cn.
¹⁹ Department of Ophthalmology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. xdsun@sjtu.edu.cn.
²⁰ National Clinical Research Center for Ophthalmic Diseases, Shanghai, China. xdsun@sjtu.edu.cn.
²¹ Shanghai Key Laboratory of Fundus Diseases, Shanghai, China. xdsun@sjtu.edu.cn.

^# Contributed equally.

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.

MeSH terms

Animals
Carbon Monoxide / metabolism
Diabetic Retinopathy / metabolism
Diabetic Retinopathy / pathology
Endothelial Cells / metabolism
Endothelial Protein C Receptor* / genetics
Endothelial Protein C Receptor* / metabolism
Female
Heme Oxygenase-1 / genetics
Heme Oxygenase-1 / metabolism
Heme* / metabolism
Humans
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Retinal Neovascularization* / genetics
Retinal Neovascularization* / metabolism
Retinal Neovascularization* / pathology

Substances

Heme
Endothelial Protein C Receptor
Heme Oxygenase-1
Carbon Monoxide
PROCR protein, human

Abstract

MeSH terms

Substances

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