Endothelial FAK is essential for vascular network stability, cell survival, and lamellipodial formation.
Endothelial FAK is essential for vascular network stability, cell survival, and lamellipodial formation.
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DOI：
10.1083/jcb.200506184
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发表时间：
2006-01-02
影响因子：
7.8
通讯作者：
Wang, Rong
中科院分区：
文献类型：
--
作者：
Braren, Rickmer;Hu, Huiqing;Kim, Yung Hae;Beggs, Hilary E;Reichardt, Louis F;Wang, Rong
血管网的形态发生需要动态的血管生长和退化。为了研究这一过程的细胞机制，我们使用Tie 2-Cre小鼠在内皮细胞（EC）中删除了粘着斑激酶（FAK），一种关键的信号传导介质。靶向FAK消耗在发育早期有效发生，其中突变体表现出独特且不规则的血管系统，导致胚胎第10.5天至11.5天之间的出血和死亡。在e9.5出现任何其他可检测到的异常之前，卵黄囊中的毛细血管和毛细血管间空间扩张，并且外植体证明缺陷是由FAK的丢失而不是器官衰竭引起的。在外植体血管形成过程中监测EC行为的延时显微镜显示增殖或迁移没有明显减少，但显示细胞收缩和死亡增加，导致血管生长减少和血管退化增加。与此表型相一致，来自突变胚胎的EC表现出异常的片状伪足延伸，改变肌动蛋白细胞骨架，和非极化细胞运动。这项研究表明，FAK是至关重要的血管形态发生和EC的生存和形态的调节。
Morphogenesis of a vascular network requires dynamic vessel growth and regression. To investigate the cellular mechanism underlying this process, we deleted focal adhesion kinase (FAK), a key signaling mediator, in endothelial cells (ECs) using Tie2-Cre mice. Targeted FAK depletion occurred efficiently early in development, where mutants exhibited a distinctive and irregular vasculature, resulting in hemorrhage and lethality between embryonic day (e) 10.5 and 11.5. Capillaries and intercapillary spaces in yolk sacs were dilated before any other detectable abnormalities at e9.5, and explants demonstrate that the defects resulted from the loss of FAK and not from organ failure. Time-lapse microscopy monitoring EC behavior during vascular formation in explants revealed no apparent decrease in proliferation or migration but revealed increases in cell retraction and death leading to reduced vessel growth and increased vessel regression. Consistent with this phenotype, ECs derived from mutant embryos exhibited aberrant lamellipodial extensions, altered actin cytoskeleton, and nonpolarized cell movement. This study reveals that FAK is crucial for vascular morphogenesis and the regulation of EC survival and morphology.