Notch3 is critical for proper angiogenesis and mural cell investment.
Notch3 is critical for proper angiogenesis and mural cell investment.
复制标题
DOI：
10.1161/circresaha.110.218271
复制
发表时间：
2010-10-01
影响因子：
20.1
通讯作者：
Lilly B
中科院分区：
文献类型：
--
作者：
Liu H;Zhang W;Kennard S;Caldwell RB;Lilly B
内皮细胞和壁细胞（平滑肌细胞或周细胞）的异型相互作用对于血管的组装、成熟和随后的功能至关重要。然而，其关联的分子机制尚未完全确定。我们之前的体外研究表明，在壁细胞中表达的Notch 3介导这些细胞-细胞相互作用。为了评估Notch 3对体内血管形成的意义，我们研究了其在视网膜血管生成中的作用。我们发现Notch 3缺陷小鼠表现出视网膜血管化减少，出芽和血管分支减少。此外，Notch 3缺失损害壁细胞投资，导致血管覆盖的进行性损失。在氧诱导的视网膜病变（OIR）模型中，我们证明了Notch 3在缺氧中被诱导，有趣的是，Notch 3缺失小鼠的视网膜中病理性新血管形成减少。OIR介质的分析显示，在Notch 3不存在的情况下，血管生成素-2的表达显著降低。此外，体外实验表明Notch 3足以诱导血管生成素-2，并且在HIF 1 α存在下这种表达额外增强。这些结果提供了令人信服的证据，即Notch 3对于壁细胞的投资是重要的，并且是发育和病理血管形成的关键调节剂。
The heterotypic interactions of endothelial cells and mural cells (smooth muscle cells or pericytes) are crucial for assembly, maturation and subsequent function of blood vessels. Yet, the molecular mechanisms underlying their association have not been fully defined. Our previous in vitro studies indicated that Notch3, which is expressed in mural cells, mediates these cell-cell interactions. To assess the significance of Notch3 on blood vessel formation in vivo, we investigated its role in retinal angiogenesis. We show that Notch3-deficient mice exhibit reduced retinal vascularization, with diminished sprouting and vascular branching. Moreover, Notch3 deletion impairs mural cell investment, resulting in progressive loss of vessel coverage. In an oxygen-induced retinopathy (OIR) model, we demonstrate that Notch3 is induced in hypoxia and interestingly, pathological neovascularization is decreased in retinas of Notch3 null mice. Analysis of OIR mediators revealed that Angiopoietin-2 expression is significantly reduced in the absence of Notch3. Further, in vitro experiments showed that Notch3 is sufficient for Angiopoietin-2 induction, and this expression is additionally enhanced in the presence of HIF1α. These results provide compelling evidence that Notch3 is important for the investment of mural cells and is a critical regulator of developmental and pathological blood vessel formation.