Endothelial cells-targeted soluble human Delta-like 4 suppresses both physiological and pathological ocular angiogenesis  

作　　者：YAN XianChun YANG ZiYan CHEN Yan LI Na WANG Li DOU GuoRui LIU Yuan DUAN JuanLi FENG Lei DENG SanMing HAN Hua ZHANG Ping 

机构地区：[1]State Key Laboratory of Cancer Biology, Department of Medical Genetics and Developmental Biology, Fourth Military Medical University [2]Department of Oncology, Xijing Hospital Fourth Military Medical University [3]Department of Ophthalmology, Xijing Hospital, Fourth Military Medical University

出　　处：《Science China(Life Sciences)》2015年第5期425-431,共7页中国科学（生命科学英文版）

基　　金：supported by the National Natural Science Foundation of China(31370769,81200707,91339115,31301194)

摘　　要：Due to its essential roles in angiogenesis, Notch pathway has emerged as an attractive target for the treatment of pathologic angiogenesis. Although both activation and blockage of Notch signal can impede angiogenesis, activation of Notch signal may be more promising because it was shown that long-term Notch signal blockage resulted in vessel neoplasm. However, an in vivo deliverable Notch ligand with highly efficient Notch-activating capacity has not been developed. Among all the Notch ligands, Delta-like4(Dll4) is specifically involved in angiogenesis. In this study, we generated a novel soluble Notch ligand h D4 R, which consists of the Delta-Serrate-Lag-2 fragment of human Dll4 and an arginine-glycine-aspartate(RGD) motif targeting endothelial cells(ECs). We demonstrated that h D4 R could bind to ECs through its RGD motif and effectively triggered Notch signaling in ECs. Further, we confirmed that h D4 R could suppress angiogenesis in vitro as manifested by network formation assay and sprouting assay. More importantly, h D4 R efficiently repressed neonatal retinal angiogenesis and laser-induced choroidal neovascularization(CNV) as well in vivo. In conclusion, we have developed an in vivo deliverable Notch ligand h D4 R, which suppresses angiogenesis both in vitro and in vivo, thus providing a new approach to tackle excessive angiogenesis relevant disease such as CNV.Due to its essential roles in angiogenesis, Notch pathway has emerged as an attractive target for the treatment of pathologic angiogenesis. Although both activation and blockage of Notch signal can impede angiogenesis, activation of Notch signal may be more promising because it was shown that long-term Notch signal blockage resulted in vessel neoplasm. However, an in vivo deliverable Notch ligand with highly efficient Notch-activating capacity has not been developed. Among all the Notch ligands, Delta-like4 （Dll4） is specifically involved in angiogenesis. In this study, we generated a novel soluble Notch ligand hD4R, which consists of the Delta-Serrate-Lag-2 fragment of human Dll4 and an arginine-glycine-aspartate （RGD） motif targeting endothelial cells （ECs）. We demonstrated that hD4R could bind to ECs through its RGD motif and effectively triggered Notch signaling in ECs. Further, we confirmed that hD4R could suppress angiogenesis in vitro as manifested by network formation assay and sprouting assay. More importantly, hD4R efficiently repressed neonatal retinal angiogenesis and laser-induced choroidal neovascularization （CNV） as well in vivo. In conclusion, we have developed an in vivo deliverable Notch ligand hD4R, which suppresses angiogenesis both in vitro and in vivo, thus providing a new approach to tackle exces- sive angiogenesis relevant disease such as CNV.

关 键 词：Notch signal human Delta-like4 RGD ANGIOGENESIS choroidal neovascularization 

分 类 号：R77[医药卫生—眼科]