Department of Biology, University of North Carolina at Chapel Hill, Chapel Hill, USA.
Lineberger Comprehensive Cancer Center, Chapel Hill, USA.
Angiogenesis. 2021 May;24(2):387-398. doi: 10.1007/s10456-021-09777-7. Epub 2021 Mar 29.
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.
血流产生的流体切应力促使血管网络在发育过程中从活跃扩张转变为血管稳态和静止，这对于成熟血管功能很重要。本文中，我们发现 SMAD6 对于内皮细胞的血流介导反应是必需的，从而维持血管稳态。同时操纵机械感受器 Notch1 途径和 SMAD6 表达水平表明，SMAD6 位于配体诱导的 Notch 信号和转录调控的下游。从机制上讲，全长 SMAD6 蛋白对于挽救 Notch 缺失引起的血流错位是必需的。SMAD6 耗尽的内皮细胞表现出有缺陷的屏障功能，同时增殖相关基因上调，连接相关基因下调。血管原钙黏蛋白 PCDH12 受 SMAD6 上调，对于适当的血流介导的内皮细胞排列是必需的，因此位于 SMAD6 的下游。因此，SMAD6 是 Notch1 下游和 PCDH12 上游血流介导信号输入的必需转导子，因为血管从血管生成表型过渡到维持稳态表型。
