Department of Molecular, Cell & Developmental Biology, University of California, Los Angeles, CA, 90095, USA.
Institute for Quantitative and Computational Biology, University of California, Los Angeles, CA, 90095, USA.
Nat Commun. 2017 Nov 20;8(1):1620. doi: 10.1038/s41467-017-01741-8.
Endothelial cells transduce mechanical forces from blood flow into intracellular signals required for vascular homeostasis. Here we show that endothelial NOTCH1 is responsive to shear stress, and is necessary for the maintenance of junctional integrity, cell elongation, and suppression of proliferation, phenotypes induced by laminar shear stress. NOTCH1 receptor localizes downstream of flow and canonical NOTCH signaling scales with the magnitude of fluid shear stress. Reduction of NOTCH1 destabilizes cellular junctions and triggers endothelial proliferation. NOTCH1 suppression results in changes in expression of genes involved in the regulation of intracellular calcium and proliferation, and preventing the increase of calcium signaling rescues the cell-cell junctional defects. Furthermore, loss of Notch1 in adult endothelium increases hypercholesterolemia-induced atherosclerosis in the descending aorta. We propose that NOTCH1 is atheroprotective and acts as a mechanosensor in adult arteries, where it integrates responses to laminar shear stress and regulates junctional integrity through modulation of calcium signaling.
内皮细胞将血流产生的机械力转导为血管稳态所必需的细胞内信号。在这里，我们表明内皮细胞 NOTCH1 对切应力有反应，并且对于维持细胞连接的完整性、细胞伸长和抑制增殖是必需的，这些表型是由层流剪切力诱导的。NOTCH1 受体位于流动的下游，并且经典的 NOTCH 信号与流体切应力的大小成比例。NOTCH1 的减少会破坏细胞连接并引发内皮细胞增殖。NOTCH1 的抑制导致参与细胞内钙和增殖调节的基因表达发生变化，并防止钙信号的增加可挽救细胞-细胞连接缺陷。此外，成年内皮细胞中 Notch1 的缺失会增加降主动脉中高胆固醇血症诱导的动脉粥样硬化。我们提出 NOTCH1 具有抗动脉粥样硬化作用，并且作为成年动脉中的机械感受器，通过调节钙信号整合对层流剪切力的反应并调节连接完整性。
