Song Hongyuan, Li Qing, Gui Xiao, Fang Ziyu, Zhou Wen, Wang Mengzhu, Jiang Yuxin, Geng Ajun, Shen Xi, Liu Yongxuan, Zhang Haorui, Nie Zheng, Zhang Lin, Zhu Huimin, Zhang Feng, Li Xuri, Luo Fanyan, Zhang Hongjian, Shen Wei, Sun Xiaodong
Department of Ophthalmology, Shanghai Changhai Hospital, Shanghai, China.
Department of Ophthalmology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Nat Commun. 2025 Feb 13;16(1):1603. doi: 10.1038/s41467-025-56810-0.
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.
病理性视网膜新生血管形成（RNV）是全球范围内导致失明的主要原因之一；然而，其潜在机制仍不清楚。在此，我们发现内皮蛋白C受体（Epcr）在RNV过程中表达增加，且其配体在增殖性糖尿病视网膜病变患者的血清或玻璃体中升高。删除内皮Epcr或使用EPCR中和抗体可改善病理性视网膜血管生成。EPCR通过血红素加氧酶1（HO-1）促进内皮血红素分解代谢和一氧化碳释放。通过删除内皮Ho-1或使用HO-1抑制剂抑制血红素分解代谢可抑制视网膜病变中的病理性血管生成。相反，补充一氧化碳可挽救内皮Epcr或Ho-1缺失后的血管生成缺陷。我们的研究结果确定EPCR依赖的内皮血红素分解代谢是病理性血管生成的重要促成因素，这可能成为治疗血管增殖性视网膜病变的潜在靶点。
