Nucleoside Diphosphate Kinase B Regulates Angiogenesis Through Modulation of Vascular Endothelial Growth Factor Receptor Type 2 and Endothelial Adherens Junction Proteins
Nucleoside Diphosphate Kinase B Regulates Angiogenesis Through Modulation of Vascular Endothelial Growth Factor Receptor Type 2 and Endothelial Adherens Junction Proteins
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DOI：
10.1161/atvbaha.114.304239
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发表时间：
2014-10-01
影响因子：
8.7
通讯作者：
Wieland, Thomas
中科院分区：
文献类型：
--
作者：
Feng, Yuxi;Gross, Shalini;Wieland, Thomas
N-核苷二磷酸激酶B（NDPK B）参与异源三聚体和单体G蛋白的活化，这些蛋白是血管生成信号传导中的关键介质。NDPKB在血管生成中的作用至今尚未明确。因此，我们分析了NDPKB血管生成的贡献及其潜在的机制，在良好的特点，在体内和体外models.Approach和Results-Zebrafish胚胎耗尽NDPKB吗啉介导的敲低。这些幼虫表现出严重的畸形，特别是在血管生成形成的血管。NDPKB缺陷型（NDPKB-/-）小鼠经受氧诱导的视网膜病变。在该模型中，NDPKB-/-小鼠视网膜前新生血管的数量与野生型同窝仔相比大幅减少。相应地，在后肢结扎后的NDPKB-/-小鼠中检测到延迟的血流恢复。在体外研究中，在人脐内皮细胞中进行小干扰RNA介导的NDPKB敲低。NDPKB耗竭损害血管内皮生长因子（VEGF）诱导的发芽，并阻碍VEGF诱导的空间再分布的VEGF受体2型和VE-钙粘蛋白在质膜。与此同时，NDPKB耗尽增加了人脐内皮细胞monolumer.Conclusions-This的渗透性是第一次报告，表明NDPKB是VEGF诱导的血管生成所需的，并有助于正确定位的VEGF受体2型和VE-钙粘蛋白在内皮adherens junctions。因此，我们的数据确定NDPKB作为一种新的分子靶点，以调节VEGF依赖的血管生成。
Objective-Nucleoside diphosphate kinase B (NDPKB) participates in the activation of heterotrimeric and monomeric G proteins, which are pivotal mediators in angiogenic signaling. The role of NDPKB in angiogenesis has to date not been defined. Therefore, we analyzed the contribution of NDPKB to angiogenesis and its underlying mechanisms in well-characterized in vivo and in vitro models.Approach and Results-Zebrafish embryos were depleted of NDPKB by morpholino-mediated knockdown. These larvae displayed severe malformations specifically in vessels formed by angiogenesis. NDPKB-deficient (NDPKB-/-) mice were subjected to oxygen-induced retinopathy. In this model, the number of preretinal neovascularizations in NDPKB-/- mice was strongly reduced in comparison with wild-type littermates. In accordance, a delayed blood flow recovery was detected in the NDPKB-/- mice after hindlimb ligation. In in vitro studies, a small interfering RNA-mediated knockdown of NDPKB was performed in human umbilical endothelial cells. NDPKB depletion impaired vascular endothelial growth factor (VEGF)-induced sprouting and hampered the VEGF-induced spatial redistributions of the VEGF receptor type 2 and VE-cadherin at the plasma membrane. Concomitantly, NDPKB depletion increased the permeability of the human umbilical endothelial cell monolayer.Conclusions-This is the first report to show that NDPKB is required for VEGF-induced angiogenesis and contributes to the correct localization of VEGF receptor type 2 and VE-cadherin at the endothelial adherens junctions. Therefore, our data identify NDPKB as a novel molecular target to modulate VEGF-dependent angiogenesis.