Endothelial protein C receptor promotes retinal neovascularization through heme catabolism
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.
Authors
- Ajun Geng (ORCID: https://orcid.org/0000-0001-7456-6566)
- Ziyu Fang (ORCID: https://orcid.org/0000-0002-7749-354X)
- Haorui Zhang (ORCID: https://orcid.org/0009-0004-0445-2810)
- Xiaodong Sun (ORCID: https://orcid.org/0000-0001-5015-0945)
- Yongxuan Liu (ORCID: https://orcid.org/0000-0002-8856-9044)
- Xi Shen (ORCID: https://orcid.org/0000-0001-9669-6521)
- Fanyan Luo (ORCID: https://orcid.org/0000-0002-1195-4585)
- Hongyuan Song (ORCID: https://orcid.org/0000-0001-8187-2799)
- Gui Xiao (ORCID: https://orcid.org/0000-0001-6001-789X)
- Xuri Li (ORCID: https://orcid.org/0000-0002-8277-0767)
- Wei Shen (ORCID: https://orcid.org/0000-0001-5754-316X)
- Feng Zhang (ORCID: https://orcid.org/0000-0002-6103-1498)
- Qing X. Li (ORCID: https://orcid.org/0000-0003-0587-1748)
- Hongjian Zhang (ORCID: https://orcid.org/0000-0002-1937-2766)
- Zheng Nie
- Mengzhu Wang (ORCID: https://orcid.org/0000-0002-8151-194X)
- Yuxin Jiang (ORCID: https://orcid.org/0000-0002-9797-5116)
- Lin Zhang (ORCID: https://orcid.org/0000-0001-9750-7614)
- Wen Zhou
- Huimin Zhu
Institutions
- Tongji University (CN)
- Central South University (CN)
- University of Shanghai for Science and Technology (CN)
- Sun Yat-sen University (CN)
- Second Military Medical University (CN)
- Shanghai Jiao Tong University (CN)
- Ruijin Hospital (CN)
- National Clinical Research Center for Digestive Diseases (CN)
- Fosun Pharma (China) (CN)
- Changhai Hospital (CN)
- Center for Excellence in Molecular Cell Science (CN)
- National Clinical Research (US)
- Shanghai First People's Hospital (CN)
- Second Affiliated Hospital of Nanjing Medical University (CN)
- Wuxi People's Hospital (CN)
- Xiangya Hospital Central South University (CN)
- University of Chinese Academy of Sciences (CN)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-02-13
- DOI
- https://doi.org/10.1038/s41467-025-56810-0
- Citations
- 9
- Primary Topic
- Heme Oxygenase-1 and Carbon Monoxide
- Type
- article
- Field-Weighted Citation Impact
- 7.25
Funders
- Shanghai Science and Technology Development Foundation
- National Natural Science Foundation of China
- Shanghai Municipal Education Commission