Polo-like kinase 2 regulates angiogenic sprouting and blood vessel development.
Polo-like kinase 2 regulates angiogenic sprouting and blood vessel development.
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DOI：
10.1016/j.ydbio.2015.05.011
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发表时间：
2015-08-15
影响因子：
2.7
通讯作者：
Chi NC
中科院分区：
文献类型：
--
作者：
Yang H;Fang L;Zhan R;Hegarty JM;Ren J;Hsiai TK;Gleeson JG;Miller YI;Trejo J;Chi NC
血管生成依赖于特殊的内皮细胞尖端细胞向引导线索延伸，以引导生长的血管。虽然许多控制这种定向内皮细胞萌发的信号通路是众所周知的，但介导这一过程的具体细胞机制仍未完全阐明。在这里，我们展示了Polo-like kinase2(PLK2)调节Rap1的活性，以引导内皮细胞片状脂膜的形成和随后的血管生成萌发。结合斑马鱼血管发育的高分辨率体内成像和人脐静脉内皮细胞(HUVEC)的体外培养系统，我们观察到PLK2功能的丧失导致内皮细胞出芽和迁移减少，而PLK2的过表达促进了血管生成。此外，我们还发现PLK2可能通过与PDZ-Global结合来调控内皮细胞片状脂膜形成和细胞外基质附着过程中RAP1的活性，从而控制血管生成。与这些发现一致的是，结构性活性RAP1可以修复在斑马鱼和HUVEC PLK2基因敲除中观察到的内皮细胞发芽缺陷。总体而言，这些发现揭示了一条保守的PLK2-RAP1途径，该途径对于调节内皮细胞的行为至关重要，以确保脊椎动物适当的血管发育和模式。
Angiogenesis relies on specialized endothelial tip cells to extend toward guidance cues in order to direct growing blood vessels. Although many of the signaling pathways that control this directional endothelial sprouting are well known, the specific cellular mechanisms that mediate this process remain to be fully elucidated. Here, we show that Polo-like kinase 2 (PLK2) regulates Rap1 activity to guide endothelial tip cell lamellipodia formation and subsequent angiogenic sprouting. Using a combination of high-resolution in vivo imaging of zebrafish vascular development and a human umbilical vein endothelial cell (HUVEC) in vitro cell culture system, we observed that loss of PLK2 function resulted in a reduction in endothelial cell sprouting and migration, whereas overexpression of PLK2 promoted angiogenesis. Furthermore, we discovered that PLK2 may control angiogenic sprouting by binding to PDZ-GEF to regulate RAP1 activity during endothelial cell lamellipodia formation and extracellular matrix attachment. Consistent with these findings, constitutively active RAP1 could rescue the endothelial cell sprouting defects observed in zebrafish and HUVEC PLK2 knockdowns. Overall, these findings reveal a conserved PLK2-RAP1 pathway that is crucial to regulate endothelial tip cell behavior in order to ensure proper vascular development and patterning in vertebrates.