Semaphorin 3E-Plexin-D1 signaling regulates VEGF function in developmental angiogenesis via a feedback mechanism
Semaphorin 3E-Plexin-D1 signaling regulates VEGF function in developmental angiogenesis via a feedback mechanism
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DOI：
10.1101/gad.2042011
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发表时间：
2011-07-01
影响因子：
10.5
通讯作者：
Gu, Chenghua
中科院分区：
文献类型：
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作者：
Kim, Jiha;Oh, Won-Jong;Gu, Chenghua
血管网络通常是通过血管生成形成的，在该过程中，内皮细胞从预先存在的血管中萌芽而形成新血管。这个过程是由血管内皮生长因子（VEGF）介导的尖端细胞选择和随后的血管生成启动的。令人惊讶的是，我们发现 VEGF 直接控制 Plexin-D1 的表达，Plexin-D1 是传统排斥性轴突导向信号信号蛋白 3E (Sema3E) 的受体。然后，Sema3E-Plexin-D1 信号传导负向调节 VEGF 诱导的 Delta-like 4 (Dll4)-Notch 信号传导通路的活性，该通路控制尖端细胞和茎细胞之间的细胞命运决定。使用小鼠视网膜作为模型系统，我们发现 Plexin-D1 在活跃萌芽血管前端的内皮细胞中选择性表达，并且其表达受到周围组织分泌的 VEGF 的严格控制。因此，尽管视网膜神经元分泌的Sema3E均匀分布在整个视网膜中，但Sema3-EPlexin-D1信号传导在空间上受到VEGF通过其对Plexin-D1的调节的控制。此外，我们发现 Sema3E 和 Plexin-D1 功能的获得和丧失会破坏视网膜血管系统中正常的 Dll4 表达、Notch 活性和尖端/茎细胞分布。最后，缺乏 sema3E 或 plexin-D1 的小鼠的视网膜血管系统具有不均匀的生长前沿、分支较少的血管网络以及 dll4 阳性细胞的异常分布。降低突变小鼠的 Notch 活性可以逆转这种缺陷，从而证实了 Dll4-Notch 信号传导受 Sema3E-Plexin-D1 调节并且是其体内功能所必需的观察结果。总之，这些数据揭示了 Sema3E-Plexin-D1 功能通过 VEGF 诱导的反馈机制调节血管生成的新作用。
Blood vessel networks are typically formed by angiogenesis, a process in which new vessels form by sprouting of endothelial cells from pre-existing vessels. This process is initiated by vascular endothelial growth factor (VEGF)mediated tip cell selection and subsequent angiogenic sprouting. Surprisingly, we found that VEGF directly controls the expression of Plexin-D1, the receptor for the traditional repulsive axon guidance cue, semaphorin 3E (Sema3E). Sema3E-Plexin-D1 signaling then negatively regulates the activity of the VEGF-induced Delta-like 4 (Dll4)-Notch signaling pathway, which controls the cell fate decision between tip and stalk cells. Using the mouse retina as a model system, we show that Plexin-D1 is selectively expressed in endothelial cells at the front of actively sprouting blood vessels and its expression is tightly controlled by VEGF secreted by surrounding tissues. Therefore, although the Sema3E secreted by retinal neurons is evenly distributed throughout the retina, Sema3-EPlexin- D1 signaling is spatially controlled by VEGF through its regulation of Plexin-D1. Moreover, we show that gain and loss of function of Sema3E and Plexin-D1 disrupts normal Dll4 expression, Notch activity, and tip/stalk cell distribution in the retinal vasculature. Finally, the retinal vasculature of mice lacking sema3E or plexin-D1 has an uneven growing front, a less-branched vascular network, and abnormal distribution of dll4-positive cells. Lowering Notch activity in the mutant mice can reverse this defect, solidifying the observation that Dll4-Notch signaling is regulated by Sema3E-Plexin-D1 and is required for its function in vivo. Together, these data reveal a novel role of Sema3E-Plexin-D1 function in modulating angiogenesis via a VEGF-induced feedback mechanism.