PP2A regulatory subunit Bα controls endothelial contractility and vessel lumen integrity via regulation of HDAC7
PP2A regulatory subunit Bα controls endothelial contractility and vessel lumen integrity via regulation of HDAC7
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DOI：
10.1038/emboj.2013.187
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发表时间：
2013-09-11
期刊：
影响因子：
11.4
通讯作者：
Dequiedt, Franck
中科院分区：
文献类型：
--
作者：
Martin, Maud;Geudens, Ilse;Dequiedt, Franck
为了给组织提供营养和氧气，心血管系统形成了一个无缝的、分级分支的管腔化管道网络。在这里，我们表明，维护专利的血管腔需要B α调节亚基的蛋白磷酸酶2A（PP 2A）。斑马鱼中B α的缺乏妨碍了血管腔的稳定，导致灌注缺陷。类似地，在培养的EC中PP 2A-B α的失活由于细胞骨架动力学、肌动球蛋白收缩性和细胞-细胞外基质（ECM）接触的成熟的改变而诱导小管形成失败。从机制上讲，我们表明PP 2A-B α控制HDAC 7的活性，HDAC 7是血管稳定性的重要转录调节因子。在不存在PP 2A-B α的情况下，HDAC 7的转录抑制被消除，导致细胞骨架衔接蛋白ArgBP 2的表达增强。ArgBP 2过度激活RhoA，导致EC肌动球蛋白细胞骨架的不充分重排。这项研究揭示了PP 2A全酶在发育中的第一个特定作用：PP 2A-B alpha/HDAC 7/ArgBP 2轴通过平衡内皮细胞骨架动力学和细胞-基质粘附来维持血管腔。
To supply tissues with nutrients and oxygen, the cardiovascular system forms a seamless, hierarchically branched, network of lumenized tubes. Here, we show that maintenance of patent vessel lumens requires the B alpha regulatory subunit of protein phosphatase 2A (PP2A). Deficiency of B alpha in zebrafish precludes vascular lumen stabilization resulting in perfusion defects. Similarly, inactivation of PP2A-B alpha in cultured ECs induces tubulogenesis failure due to alteration of cytoskeleton dynamics, actomyosin contractility and maturation of cell-extracellular matrix (ECM) contacts. Mechanistically, we show that PP2A-B alpha controls the activity of HDAC7, an essential transcriptional regulator of vascular stability. In the absence of PP2A-B alpha, transcriptional repression by HDAC7 is abrogated leading to enhanced expression of the cytoskeleton adaptor protein ArgBP2. ArgBP2 hyperactivates RhoA causing inadequate rearrangements of the EC actomyosin cytoskeleton. This study unravels the first specific role for a PP2A holoenzyme in development: the PP2A-B alpha/HDAC7/ArgBP2 axis maintains vascular lumens by balancing endothelial cytoskeletal dynamics and cell-matrix adhesion.