Endothelial cells-targeted soluble human Delta-like 4 suppresses both physiological and pathological ocular angiogenesis
Endothelial cells-targeted soluble human Delta-like 4 suppresses both physiological and pathological ocular angiogenesis
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内皮细胞靶向可溶性人 Delta-like 4 抑制生理和病理性眼部血管生成
DOI：
10.1007/s11427-015-4834-3
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发表时间：
2015-05-01
影响因子：
9.1
通讯作者：
Zhang Ping
中科院分区：
文献类型：
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作者：
Yan XianChun;Yang ZiYan;Zhang Ping
由于其在血管生成中的重要作用，Notch通路已成为治疗病理性血管生成的一个有吸引力的靶点。虽然Notch信号的激活和阻断都可以阻碍血管生成，但激活Notch信号可能更有希望，因为有研究表明，长期的Notch信号阻断会导致血管肿瘤。然而，目前还没有开发出一种具有高效Notch激活能力的、可在体内传递的Notch配体。在所有Notch配体中，Delta-like4 （Dll4）特异参与血管生成。在这项研究中，我们生成了一种新的可溶性Notch配体hD4R，它由人类Dll4的delta - serate - lag -2片段和靶向内皮细胞（ECs）的精氨酸-甘氨酸-天门氨酸（RGD）基序组成。我们证明了hD4R可以通过其RGD基序与ECs结合，并有效地触发ECs中的Notch信号。此外，我们通过网络形成实验和发芽实验证实了hD4R可以抑制体外血管生成。更重要的是，hD4R在体内也能有效抑制新生儿视网膜血管生成和激光诱导的脉络膜新生血管（CNV）。综上所述，我们开发了一种体内可传递的Notch配体hD4R，该配体可抑制体外和体内的血管生成，从而为解决过度血管生成相关疾病（如CNV）提供了一种新的方法。
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, anin vivodeliverable 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 angiogenesisin vitroas manifested by network formation assay and sprouting assay. More importantly, hD4R efficiently repressed neonatal retinal angiogenesis and laser-induced choroidal neovascularization (CNV) as wellin vivo. In conclusion, we have developed anin vivodeliverable Notch ligand hD4R, which suppresses angiogenesis bothin vitroandin vivo, thus providing a new approach to tackle excessive angiogenesis relevant disease such as CNV.