Max-Delbrück-Center for Molecular Medicine, Berlin, Germany.
Vascular Biology Laboratory, Lincoln's Inn Fields Laboratories, London Research Institute - Cancer Research UK, London, United Kingdom.
Elife. 2018 Feb 5;7:e31037. doi: 10.7554/eLife.31037.
Formation of blood vessel networks by sprouting angiogenesis is critical for tissue growth, homeostasis and regeneration. How endothelial cells arise in adequate numbers and arrange suitably to shape functional vascular networks is poorly understood. Here we show that YAP/TAZ promote stretch-induced proliferation and rearrangements of endothelial cells whilst preventing bleeding in developing vessels. Mechanistically, YAP/TAZ increase the turnover of VE-Cadherin and the formation of junction associated intermediate lamellipodia, promoting both cell migration and barrier function maintenance. This is achieved in part by lowering BMP signalling. Consequently, the loss of YAP/TAZ in the mouse leads to stunted sprouting with local aggregation as well as scarcity of endothelial cells, branching irregularities and junction defects. Forced nuclear activity of TAZ instead drives hypersprouting and vascular hyperplasia. We propose a new model in which YAP/TAZ integrate mechanical signals with BMP signaling to maintain junctional compliance and integrity whilst balancing endothelial cell rearrangements in angiogenic vessels.
血管生成是血管网络形成的关键，它对于组织生长、稳态和再生至关重要。内皮细胞如何以足够的数量出现并适当排列以形成功能性血管网络，目前还知之甚少。在这里，我们发现 YAP/TAZ 促进了伸展诱导的内皮细胞增殖和重排，同时防止了发育中的血管出血。在机制上，YAP/TAZ 增加了 VE-钙黏蛋白的周转率和连接相关中间片状伪足的形成，从而促进了细胞迁移和屏障功能的维持。这在一定程度上是通过降低 BMP 信号来实现的。因此，在小鼠中敲除 YAP/TAZ 会导致芽生受阻，出现局部聚集以及内皮细胞数量减少、分支不规则和连接缺陷。TAZ 的核活性强制增加会导致过度芽生和血管增生。我们提出了一个新的模型，其中 YAP/TAZ 将机械信号与 BMP 信号整合在一起，以维持连接的顺应性和完整性，同时平衡血管生成过程中内皮细胞的重排。
