Molecular/Cancer Biology Laboratory, Research Programs Unit, Institute for Molecular Medicine Finland and Helsinki University Central Hospital, Helsinki, Finland.
Blood. 2011 Jul 28;118(4):1154-62. doi: 10.1182/blood-2010-11-317800. Epub 2011 May 12.
Notch signaling plays a central role in cell-fate determination, and its role in lateral inhibition in angiogenic sprouting is well established. However, the role of Notch signaling in lymphangiogenesis, the growth of lymphatic vessels, is poorly understood. Here we demonstrate Notch pathway activity in lymphatic endothelial cells (LECs), as well as induction of delta-like ligand 4 (Dll4) and Notch target genes on stimulation with VEGF or VEGF-C. Suppression of Notch signaling by a soluble form of Dll4 (Dll4-Fc) synergized with VEGF in inducing LEC sprouting in 3-dimensional (3D) fibrin gel assays. Expression of Dll4-Fc in adult mouse ears promoted lymphangiogenesis, which was augmented by coexpressing VEGF. Lymphangiogenesis triggered by Notch inhibition was suppressed by a monoclonal VEGFR-2 Ab as well as soluble VEGF and VEGF-C/VEGF-D ligand traps. LECs transduced with Dll4 preferentially adopted the tip cell position over nontransduced cells in 3D sprouting assays, suggesting an analogous role for Dll4/Notch in lymphatic and blood vessel sprouting. These results indicate that the Notch pathway controls lymphatic endothelial quiescence, and explain why LECs are poorly responsive to VEGF compared with VEGF-C. Understanding the role of the Notch pathway in lymphangiogenesis provides further insight for the therapeutic manipulation of the lymphatic vessels.
Notch 信号通路在细胞命运决定中发挥着核心作用，其在血管生成发芽中的侧向抑制作用已得到充分证实。然而，Notch 信号通路在淋巴管生成（淋巴管的生长）中的作用还知之甚少。在这里，我们证明了 Notch 途径在淋巴管内皮细胞（LEC）中的活性，以及在刺激 VEGF 或 VEGF-C 时诱导 delta-like 配体 4（Dll4）和 Notch 靶基因的表达。可溶性 Dll4（Dll4-Fc）抑制 Notch 信号通路与 VEGF 协同作用，在 3 维（3D）纤维蛋白凝胶测定中诱导 LEC 发芽。Dll4-Fc 在成年小鼠耳朵中的表达促进了淋巴管生成，而与 VEGF 共表达则增强了淋巴管生成。Notch 抑制引发的淋巴管生成被单克隆 VEGFR-2 Ab 以及可溶性 VEGF 和 VEGF-C/VEGF-D 配体陷阱所抑制。在 3D 发芽测定中，转导 Dll4 的 LEC 比未转导的细胞更倾向于采用尖端细胞位置，这表明 Dll4/Notch 在淋巴管和血管发芽中具有类似的作用。这些结果表明，Notch 途径控制淋巴管内皮细胞的静止状态，并解释了为什么与 VEGF-C 相比，LEC 对 VEGF 的反应性较差。了解 Notch 途径在淋巴管生成中的作用为淋巴管的治疗性操纵提供了进一步的见解。
