Department of Molecular, Cell and Developmental Biology.
Molecular Biology Institute, University of California, Los Angeles, California, USA.
Curr Opin Hematol. 2018 May;25(3):212-218. doi: 10.1097/MOH.0000000000000425.
The formation of a hierarchical vascular network is a complex process that requires precise temporal and spatial integration of several signaling pathways. Amongst those, Notch has emerged as a key regulator of multiple steps that expand from endothelial sprouting to arterial specification and remains relevant in the adult. This review aims to summarize major concepts and rising hypotheses on the role of Notch signaling in the endothelium.
A wealth of new information has helped to clarify how Notch signaling cooperates with other pathways to orchestrate vascular morphogenesis, branching, and function. Endothelial vascular endothelial growth factor, C-X-C chemokine receptor type 4, and nicotinamide adenine dinucleotide phosphate oxidase 2 have been highlighted as key regulators of the pathway. Furthermore, blood flow forces during vascular development induce Notch1 signaling to suppress endothelial cell proliferation, enhance barrier function, and promote arterial specification. Importantly, Notch1 has been recently recognized as an endothelial mechanosensor that is highly responsive to the level of shear stress to enable differential Notch activation in distinct regions of the vessel wall and suppress inflammation.
Although it is well accepted that the Notch signaling pathway is essential for vascular morphogenesis, its contributions to the homeostasis of adult endothelium were uncovered only recently. Furthermore, its exquisite regulation by flow and impressive interface with multiple signaling pathways indicates that Notch is at the center of a highly interactive web that integrates both physical and chemical signals to ensure vascular stability.
分层血管网络的形成是一个复杂的过程，需要几个信号通路的精确时空整合。其中，Notch 已成为从内皮芽生到动脉特化扩展的多个步骤的关键调节剂，并在成年期仍然相关。本综述旨在总结 Notch 信号在血管内皮中的作用的主要概念和新假设。
大量新信息帮助阐明了 Notch 信号如何与其他途径合作，以协调血管形态发生、分支和功能。内皮血管内皮生长因子、C-X-C 趋化因子受体 4 和烟酰胺腺嘌呤二核苷酸磷酸氧化酶 2 已被突出为该途径的关键调节剂。此外，血管发育过程中的血流力诱导 Notch1 信号抑制内皮细胞增殖、增强屏障功能并促进动脉特化。重要的是， Notch1 最近被认为是一种内皮机械感受器，对剪切应力水平高度敏感，能够在血管壁的不同区域激活差异 Notch，并抑制炎症。
虽然 Notch 信号通路对于血管形态发生至关重要，但它对成年内皮细胞的稳态的贡献最近才被发现。此外，它受到流动的精细调节以及与多种信号通路的令人印象深刻的接口表明， Notch 处于一个高度交互的网络的中心，该网络整合了物理和化学信号，以确保血管稳定性。
