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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Haploinsufficiency of delta-like 4 ligand results in embryonic lethality due to major defects in arterial and vascular development.
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Haploinsufficiency of delta-like 4 ligand results in embryonic lethality due to major defects in arterial and vascular development.

机译：由于动脉和血管发育的主要缺陷，δ样4配体的单倍剂量不足导致胚胎致死率。

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摘要

Vascular development depends on the highly coordinated actions of a variety of angiogenic regulators, most of which apparently act downstream of vascular endothelial growth factor (VEGF). One potential such regulator is delta-like 4 ligand (Dll4), a recently identified partner for the Notch receptors. We generated mice in which the Dll4 gene was replaced with a reporter gene, and found that Dll4 expression is initially restricted to large arteries in the embryo, whereas in adult mice and tumor models, Dll4 is specifically expressed in smaller arteries and microvessels, with a striking break in expression just as capillaries merge into venules. Consistent with these arterial-specific expression patterns, heterozygous deletion of Dll4 resulted in prominent albeit variable defects in arterial development (reminiscent of those in Notch knockouts), including abnormal stenosis and atresia of the aorta, defective arterial branching from the aorta, and even arterial regression, with occasional extension of thedefects to the venous circulation; also noted was gross enlargement of the pericardial sac and failure to remodel the yolk sac vasculature. These striking phenotypes resulting from heterozygous deletion of Dll4 indicate that vascular development may be as sensitive to subtle changes in Dll4 dosage as it is to subtle changes in VEGF dosage, because VEGF accounts for the only other example of haploid insufficiency, resulting in obvious vascular abnormalities. In summary, Dll4 appears to be a major trigger of Notch receptor activities previously implicated in arterial and vascular development, and it may represent a new opportunity for pro- and anti-angiogenic therapies.
机译：血管发育取决于多种血管生成调节剂的高度协调作用，其中大多数显然作用于血管内皮生长因子（VEGF）的下游。一种潜在的这种调节剂是δ样4配体（Dll4），其是最近发现的Notch受体的伴侣。我们生成了其中Dll4基因被报道基因取代的小鼠，发现Dll4的表达最初仅限于胚胎中的大动脉，而在成年小鼠和肿瘤模型中，Dll4则在较小的动脉和微血管中特异性表达，并具有在毛细血管融合成小静脉的过程中，表达方式发生了明显的变化。与这些动脉特异性表达模式一致，Dll4的杂合缺失导致动脉发育过程中出现明显的可变缺陷（让人想起Notch基因敲除的那些），包括异常的狭窄和主动脉闭锁，有缺陷的主动脉分支分支，甚至是动脉消退，偶尔将缺陷扩大到静脉循环；还注意到心包囊明显肿大，卵黄囊脉管系统无法重塑。 Dll4杂合缺失导致的这些显着表型表明，血管发育对Dll4剂量的细微变化可能与对VEGF剂量的细微变化一样敏感，因为VEGF是单倍体功能不全的唯一另一个例子，导致明显的血管异常。总之，Dll4似乎是Notch受体活性的主要触发因素，以前与动脉和血管发育有关，它可能代表促血管生成和抗血管生成治疗的新机会。

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