Vascular morphogenesis requires persistent endothelial cell motility that is responsive to diverse and dynamic mechanical stimuli. Here, we interrogated the mechanotransductive feedback dynamics that govern endothelial cell motility and vascular morphogenesis. We show that the transcriptional regulators, YAP and TAZ, are activated by mechanical cues to transcriptionally limit cytoskeletal and focal adhesion maturation, forming a conserved mechanotransductive feedback loop that mediates human endothelial cell motility in vitro and zebrafish intersegmental vessel (ISV) morphogenesis in vivo. This feedback loop closes in 4 hours, achieving cytoskeletal equilibrium in 8 hours. Feedback loop inhibition arrested endothelial cell migration in vitro and ISV morphogenesis in vivo. Inhibitor washout at 3 hrs, prior to feedback loop closure, restored vessel growth, but washout at 8 hours, longer than the feedback timescale, did not, establishing lower and upper bounds for feedback kinetics in vivo. Mechanistically, YAP and TAZ induced transcriptional suppression of RhoA signaling to maintain dynamic cytoskeletal equilibria. Together, these data establish the mechanoresponsive dynamics of a transcriptional feedback loop necessary for persistent endothelial cell migration and vascular morphogenesis.

中文翻译：

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内皮细胞运动和血管形态发生的力传导反馈控制

血管形态发生需要持续的内皮细胞运动，对多种动态机械刺激做出反应。在这里，我们询问了控制内皮细胞运动和血管形态发生的力传导反馈动力学。我们发现转录调节因子 YAP 和 TAZ 被机械信号激活，在转录上限制细胞骨架和粘着斑成熟，形成保守的机械传导反馈回路，介导体外人内皮细胞运动和体内斑马鱼节间血管（ISV）形态发生。该反馈回路在 4 小时内关闭，在 8 小时内实现细胞骨架平衡。反馈环抑制可阻止体外内皮细胞迁移和体内 ISV 形态发生。反馈环路闭合前 3 小时的抑制剂清洗可恢复血管生长，但长于反馈时间尺度的 8 小时清洗则不能恢复血管生长，从而建立了体内反馈动力学的下限和上限。从机制上讲，YAP 和 TAZ 诱导 RhoA 信号转录抑制，以维持动态细胞骨架平衡。这些数据共同建立了持续内皮细胞迁移和血管形态发生所必需的转录反馈环路的机械响应动力学。