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, Wei Shen, Xiaodong Sun
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. Pathological retinal neovascularization (RNV) is a major cause of blindness. Here, the authors show that endothelial protein C receptor (EPCR) promotes RNV through carbon monoxide derived from heme catabolism, and blocking EPCR offers therapeutic potential for the treating RNV.