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 () and Xiaodong Sun ()
Additional contact information
Hongyuan Song: Shanghai Changhai Hospital
Qing Li: Shanghai Changhai Hospital
Xiao Gui: Shanghai Changhai 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
Ajun Geng: Hangzhou Institute for Advanced Study
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
Wei Shen: Shanghai Changhai Hospital
Xiaodong Sun: Shanghai Jiao Tong University School of Medicine

Nature Communications, 2025, vol. 16, issue 1, 1-14

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-56810-0

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