Delta-like ligand 4 (DII4) is induced by VEGF as a negative regulator of angiogenic sprouting
Delta-like ligand 4 (DII4) is induced by VEGF as a negative regulator of angiogenic sprouting
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DOI：
10.1073/pnas.0611206104
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发表时间：
2007-02-27
影响因子：
11.1
通讯作者：
Wiegand, S. J.
中科院分区：
文献类型：
--
作者：
Lobov, I. B.;Renard, R. A.;Wiegand, S. J.
基因缺失研究表明，Delta 样配体 (Dll) 4（Notch 受体家族的跨膜配体）的单倍体不足会导致主要血管缺陷和胚胎致死。为了更好地定义 Dll4 在血管生长和分化过程中的作用，我们选择出生后视网膜作为模型，因为它的血管系统在出生后不久以高度刻板的方式发育，在此期间可以进行实验操作。我们报告说，Dll4 的表达在视网膜脉管系统中受到 VEGF 的动态调节，其中它在活跃生长的血管的前部表达最为显着。删除单个 Dll4 等位基因或通过眼内施用可溶性 Dll4-Fc 或针对 Dll4 的阻断抗体对 Dll4/Notch 信号传导进行药理抑制，都会在发育中的视网膜血管系统中产生相同的一组特征性异常，最显着的是增强血管生成和增加内皮细胞增殖，导致形成更致密和更高的视网膜血管。 相互连接的浅表毛细血管丛。在缺血性视网膜病变模型中，Dll4 阻断还增强了血管生成萌芽和失去的视网膜血管的再生，同时抑制异位病理性新血管形成。我们的数据表明，Dll4 作为负反馈调节剂由 VEGF 诱导，可防止过度旺盛的血管生成萌芽，促进分化良好的血管网络的及时形成。
Genetic deletion studies have shown that haploinsufficiency of Delta-like ligand (Dll) 4, a transmembrane ligand for the Notch family of receptors, results in major vascular defects and embryonic lethality. To better define the role of Dll4 during vascular growth and differentiation, we selected the postnatal retina as a model because its vasculature develops shortly after birth in a highly stereotypic manner, during which time it is accessible to experimental manipulation. We report that Dll4 expression is dynamically regulated by VEGF in the retinal vasculature, where it is most prominently expressed at the leading front of actively growing vessels. Deletion of a single Dll4 allele or pharmacologic inhibition of Dll4/Notch signaling by intraocular administration of either soluble Dll4-Fc or a blocking antibody against Dll4 all produced the same set of characteristic abnormalities in the developing retinal vasculature, most notably enhanced angiogenic sprouting and increased endothelial cell proliferation, resulting in the formation of a denser and more highly interconnected superficial capillary plexus. in a model of ischemic retinopathy, Dll4 blockade also enhanced angiogenic sprouting and regrowth of lost retinal vessels while suppressing ectopic pathological neovascularization. Our data demonstrate that Dll4 is induced by VEGF as a negative feedback regulator and acts to prevent overexuberant angiogenic sprouting, promoting the timely formation of a well differentiated vascular network.