title: Endothelial cells-targeted soluble human Delta-like 4 suppresses both physiological and pathological ocular angiogenesis.
abstract: 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 excessive angiogenesis relevant disease such as CNV.
authors.affiliation: State Key Laboratory of Cancer Biology, Department of Medical Genetics and Developmental Biology, Fourth Military Medical University, Xi'an, 710032, China.
authors.forename: XianChun
authors.initials: X
authors.lastname: Yan
authors.forename: ZiYan
authors.initials: Z
authors.lastname: Yang
authors.forename: Yan
authors.initials: Y
authors.lastname: Chen
authors.forename: Na
authors.initials: N
authors.lastname: Li
authors.forename: Li
authors.initials: L
authors.lastname: Wang
authors.forename: GuoRui
authors.initials: G
authors.lastname: Dou
authors.forename: Yuan
authors.initials: Y
authors.lastname: Liu
authors.forename: JuanLi
authors.initials: J
authors.lastname: Duan
authors.forename: Lei
authors.initials: L
authors.lastname: Feng
authors.forename: SanMing
authors.initials: S
authors.lastname: Deng
authors.forename: Hua
authors.initials: H
authors.lastname: Han
authors.forename: Ping
authors.initials: P
authors.lastname: Zhang
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D002135:Calcium-Binding Proteins; D020256:Choroidal Neovascularization / Q000503:physiopathology* / Q000517:prevention & control; D042783:Endothelial Cells / Q000502:physiology; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D066298:In Vitro Techniques; D036341:Intercellular Signaling Peptides and Proteins / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D008024:Ligands; D051379:Mice; D008810:Mice, Inbred C57BL; D018919:Neovascularization, Physiologic / Q000502:physiology; D009842:Oligopeptides / Q000737:chemistry / Q000235:genetics / Q000502:physiology; D010446:Peptide Fragments / Q000737:chemistry / Q000235:genetics / Q000502:physiology; D051880:Receptors, Notch / Q000502:physiology; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D015861:Retinal Neovascularization / Q000503:physiopathology* / Q000517:prevention & control; D015398:Signal Transduction; D012995:Solubility
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002135:Calcium-Binding Proteins; C424126:DLL4 protein, human; D036341:Intercellular Signaling Peptides and Proteins; D008024:Ligands; D009842:Oligopeptides; D010446:Peptide Fragments; D051880:Receptors, Notch; D011994:Recombinant Proteins; C047981:arginyl-glycyl-aspartic acid