Angiogenesis is a multistep process that requires coordinated migration, proliferation, and junction formation of vascular endothelial cells (ECs) to form new vessel branches in response to growth stimuli. Major intracellular signaling pathways that regulate angiogenesis have been well elucidated, but key transcriptional regulators that mediate these signaling pathways and control EC behaviors are only beginning to be understood. Here, we show that YAP/TAZ, a transcriptional coactivator that acts as an end effector of Hippo signaling, is critical for sprouting angiogenesis and vascular barrier formation and maturation. In mice, endothelial-specific deletion of Yap/Taz led to blunted-end, aneurysm-like tip ECs with fewer and dysmorphic filopodia at the vascular front, a hyper-pruned vascular network, reduced and disarranged distributions of tight and adherens junction proteins, disrupted barrier integrity, subsequent hemorrhage in growing retina and brain vessels, and reduced pathological choroidal neovascularization. Mechanistically, YAP/TAZ activates actin cytoskeleton remodeling, an important component of filopodia formation and junction assembly. Moreover, YAP/TAZ coordinates EC proliferation and metabolic activity by upregulating MYC signaling. Overall, these results show that YAP/TAZ plays multifaceted roles for EC behaviors, proliferation, junction assembly, and metabolism in sprouting angiogenesis and barrier formation and maturation and could be a potential therapeutic target for treating neovascular diseases.

中文翻译：

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YAP / TAZ调节发芽血管生成和血管屏障成熟

血管生成是一个多步骤的过程，需要协调一致的迁移，增殖和血管内皮细胞（EC）的连接形成，以响应生长刺激而形成新的血管分支。已经很好地阐明了调节血管生成的主要细胞内信号传导途径，但是介导这些信号传导途径和控制EC行为的关键转录调节因子才刚刚被人们理解。在这里，我们表明，YAP / TAZ，作为河马信号转导的末端效应子的转录共激活因子，对于发芽血管生成，血管屏障形成和成熟至关重要。在小鼠中，Yap / Taz的内皮细胞特异性缺失导致末端狭窄，动脉瘤样针尖EC，血管前部的丝状伪足少且畸形，血管网过度修剪，紧密和粘附连接蛋白的分布减少和混乱，屏障完整性受损，随后视网膜和大脑生长出血血管和病理性脉络膜新生血管减少。从机理上讲，YAP / TAZ激活肌动蛋白的细胞骨架重塑，这是丝状伪足形成和连接组装的重要组成部分。此外，YAP / TAZ通过上调MYC信号传导来协调EC增殖和代谢活性。总体而言，这些结果表明，YAP / TAZ在EC行为，增殖，连接组装，