Semaphorin-4A, an activator for T-cell-mediated immunity, suppresses angiogenesis via Plexin-D1
Semaphorin-4A, an activator for T-cell-mediated immunity, suppresses angiogenesis via Plexin-D1
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DOI：
10.1038/sj.emboj.7601589
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发表时间：
2007-03-07
期刊：
影响因子：
11.4
通讯作者：
Hori, Masatsugu
中科院分区：
文献类型：
--
作者：
Toyofuku, Toshihiko;Yabuki, Masanori;Hori, Masatsugu
信号蛋白最初被认为是轴突引导分子，现在被认为是广泛表达的介质，在免疫反应和器官形态发生中发挥重要作用。然而，人们对它们发挥器官特异性作用的信号通路知之甚少。在这里，我们证明了 Sema4A（之前被认为是 T 细胞介导的免疫激活剂）在内皮细胞中表达，它在体外抑制血管内皮生长因子 (VEGF) 介导的内皮细胞迁移和增殖，在体内抑制血管生成。缺乏 Sema4A 的小鼠表现出对 VEGF 或炎症刺激的反应增强的血管生成。此外，结合和功能实验表明 Plexin-D1 是内皮细胞上 Sema4A 的受体，表明 Sema4A 通过不同的受体介导的信号通路发挥器官特异性活性：内皮细胞中通过 Plexin-D1 以及 T 细胞中 T 细胞免疫球蛋白和粘蛋白结构域 2。 Sema4A 对内皮细胞的作用取决于其抑制 VEGF 介导的 Rac 激活和整合素依赖性细胞粘附的能力。因此，Sema4A-Plexin-D1 信号传导似乎负向调节血管生成。
Originally identified as axon guidance molecules, sema-phorins are now known to be widely expressed mediators that play significant roles in immune responses and organ morphogenesis. However, not much is known about the signaling pathways via which they exert their organ-specific effects. Here we demonstrate that Sema4A, previously identified as an activator of T-cell-mediated immunity, is expressed in endothelial cells, where it suppresses vascular endothelial growth factor ( VEGF)mediated endothelial cell migration and proliferation in vitro and angiogenesis in vivo. Mice lacking Sema4A exhibit enhanced angiogenesis in response to VEGF or inflammatory stimuli. In addition, binding and functional experiments revealed Plexin-D1 to be a receptor for Sema4A on endothelial cells, indicating that Sema4A exerts organ-specific activities via different receptormediated signaling pathways: via Plexin-D1 in the endothelial cells and via T-cell immunoglobulin and mucin domain-2 in T cells. The effects of Sema4A on endothelial cells are dependent on its ability to suppress VEGF-mediated Rac activation and integrin-dependent cell adhesion. It thus appears that Sema4A-Plexin-D1 signaling negatively regulates angiogenesis.