Endothelial podosome rosettes regulate vascular branching in tumour angiogenesis.
Endothelial podosome rosettes regulate vascular branching in tumour angiogenesis.
复制标题
内皮足体玫瑰花结调节肿瘤血管生成中的血管分支。
DOI：
10.1038/ncb3036
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发表时间：
2014-10
影响因子：
21.3
通讯作者：
Primo L
中科院分区：
文献类型：
--
作者：
Seano G;Chiaverina G;Gagliardi PA;di Blasio L;Puliafito A;Bouvard C;Sessa R;Tarone G;Sorokin L;Helley D;Jain RK;Serini G;Bussolino F;Primo L
血管生成内皮细胞打破血管基底膜的物理屏障并因此在成熟组织中发芽形成新血管的机制尚不清楚。在这里，我们表明，血管生成内皮细胞的特点是功能性的podosomeroxins的存在。这些细胞外基质降解和粘附结构是从头分支点的前体，代表了新血管形成的关键特征。VEGF-A刺激通过上调整合素α6β1诱导内皮细胞足状体形成。相反，α6β1整联蛋白与血管基底膜层粘连蛋白的结合通过限制α6β1整联蛋白与局灶性粘连并阻碍其移位至足小体而损害足小体的形成。使用离体发芽血管生成试验，转基因和基因敲除小鼠模型和人类肿瘤样品分析，我们提供的证据表明，内皮podosome roximine控制血管分支，是病理性血管生成的关键调节因子。
The mechanism by which angiogenic endothelial cells break the physical barrier of the vascular basement membrane and consequently sprout to form new vessels in mature tissues is unclear. Here, we show that the angiogenic endothelium is characterized by the presence of functional podosome rosettes. These extracellular-matrix-degrading and adhesive structures are precursors of de novo branching points and represent a key feature in the formation of new blood vessels. VEGF-A stimulation induces the formation of endothelial podosome rosettes by upregulating integrin α6β1. In contrast, the binding of α6β1 integrin to the laminin of the vascular basement membrane impairs the formation of podosome rosettes by restricting α6β1 integrin to focal adhesions and hampering its translocation to podosomes. Using an ex vivo sprouting angiogenesis assay, transgenic and knockout mouse models and human tumour sample analysis, we provide evidence that endothelial podosome rosettes control blood vessel branching and are critical regulators of pathological angiogenesis.