Fluid shear stress provided by blood flow instigates a transition from active blood vessel network expansion during development, to vascular homeostasis and quiescence that is important for mature blood vessel function. Here we show that SMAD6 is required for endothelial cell flow-mediated responses leading to maintenance of vascular homeostasis. Concomitant manipulation of the mechanosensor Notch1 pathway and SMAD6 expression levels revealed that SMAD6 functions downstream of ligand-induced Notch signaling and transcription regulation. Mechanistically, full-length SMAD6 protein was needed to rescue Notch loss-induced flow misalignment. Endothelial cells depleted for SMAD6 had defective barrier function accompanied by upregulation of proliferation-associated genes and down regulation of junction-associated genes. The vascular protocadherin PCDH12 was upregulated by SMAD6 and required for proper flow-mediated endothelial cell alignment, placing it downstream of SMAD6. Thus, SMAD6 is a required transducer of flow-mediated signaling inputs downstream of Notch1 and upstream of PCDH12, as vessels transition from an angiogenic phenotype to maintenance of a homeostatic phenotype.

血流提供的流体剪切应力促使发育过程中血管网络的活跃扩张转变为对成熟血管功能很重要的血管稳态和静止。在这里，我们表明 SMAD6 是导致维持血管稳态的内皮细胞流介导反应所必需的。同时操纵机械传感器 Notch1 通路和 SMAD6 表达水平表明 SMAD6 在配体诱导的 Notch 信号和转录调节的下游发挥作用。从机制上讲，需要全长 SMAD6 蛋白来挽救 Notch 丢失引起的流动错位。耗尽 SMAD6 的内皮细胞具有缺陷的屏障功能，伴随着增殖相关基因的上调和连接相关基因的下调。血管原钙粘蛋白 PCDH12 被 SMAD6 上调，并且需要适当的流动介导的内皮细胞排列，将其置于 SMAD6 的下游。因此，随着血管从血管生成表型过渡到维持稳态表型，SMAD6 是 Notch1 下游和 PCDH12 上游的流量介导信号输入的必需传感器。