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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Delta-like ligand 4 (Dll4) is induced by VEGF as a negative regulator of angiogenic sprouting
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Delta-like ligand 4 (Dll4) is induced by VEGF as a negative regulator of angiogenic sprouting

机译：VEGF诱导Delta样配体4（Dll4）作为血管新生的负调节剂

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摘要

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.
机译：遗传删除研究表明，Notch受体家族的跨膜配体Delta-like配体（Dll）4的单倍剂量不足会导致主要的血管缺陷和胚胎致死率。为了更好地定义Dll4在血管生长和分化中的作用，我们选择了产后视网膜作为模型，因为它的脉管系统在出生后不久就以高度定型的方式发育，在此期间可以进行实验操作。我们报告Dll4表达是由视网膜血管系统中的VEGF动态调节的，它在活跃的血管生长的最前沿最显着地表达。通过眼内施用可溶性Dll4-Fc或针对Dll4的阻断抗体来删除单个Dll4等位基因或药理抑制Dll4 / Notch信号均在发育中的视网膜脉管系统中产生相同的一组特征异常，最明显的是增强了血管新生和增加内皮细胞增生，导致形成更紧密，更紧密相连的表层毛细血管丛。在缺血性视网膜病变模型中，Dll4阻滞剂还增强了血管生成的发芽和视网膜血管丢失的再生长，同时抑制了异位病理性新血管形成。我们的数据表明，Dll4是由VEGF诱导的负反馈调节剂，可防止过度旺盛的血管新生，促进及时分化的血管网络的形成。

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