Vascular Biology Program, Boston Children's Hospital, Department of Surgery, Harvard Medical School, Boston, MA, USA.
Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden.
Dev Cell. 2020 Mar 23;52(6):779-793.e7. doi: 10.1016/j.devcel.2020.01.016. Epub 2020 Feb 13.
Transcriptional mechanisms that drive angiogenesis and organotypic vascular endothelial cell specialization are poorly understood. Here, we show that retinal endothelial sphingosine 1-phosphate receptors (S1PRs), which restrain vascular endothelial growth factor (VEGF)-induced angiogenesis, spatially restrict expression of JunB, a member of the activator protein 1 (AP-1) family of transcription factors (TFs). Mechanistically, VEGF induces JunB expression at the sprouting vascular front while S1PR-dependent vascular endothelial (VE)-cadherin assembly suppresses JunB expression in the nascent vascular network, thus creating a gradient of this TF. Endothelial-specific JunB knockout mice showed diminished expression of neurovascular guidance genes and attenuated retinal vascular network progression. In addition, endothelial S1PR signaling is required for normal expression of β-catenin-dependent genes such as TCF/LEF1 and ZIC3 TFs, transporters, and junctional proteins. These results show that S1PR signaling restricts JunB function to the expanding vascular front, thus creating an AP-1 gradient and enabling organotypic endothelial cell specialization of the vascular network.
转录机制驱动血管生成和器官样血管内皮细胞特化，但目前对此知之甚少。在这里，我们表明，视网膜内皮鞘氨醇 1-磷酸受体（S1PR）抑制血管内皮生长因子（VEGF）诱导的血管生成，空间限制了激活蛋白 1（AP-1）家族转录因子（TFs）成员 JunB 的表达。从机制上讲，VEGF 在萌芽血管前沿诱导 JunB 表达，而 S1PR 依赖性血管内皮（VE）-钙粘蛋白组装抑制新生血管网络中的 JunB 表达，从而形成该 TF 的梯度。内皮特异性 JunB 敲除小鼠表现出神经血管导向基因表达减少和视网膜血管网络进展减弱。此外，内皮 S1PR 信号对于β-连环蛋白依赖性基因（如 TCF/LEF1 和 ZIC3 TF、转运蛋白和连接蛋白）的正常表达是必需的。这些结果表明，S1PR 信号将 JunB 功能限制在扩展的血管前沿，从而创建一个 AP-1 梯度，并使血管网络的器官样内皮细胞特化。
