State Key Laboratory of Medicinal Chemical Biology and Nankai University College of Pharmacy, and Tianjin Key Laboratory of Molecular Drug Research, Tianjin 300071, China.
Proc Natl Acad Sci U S A. 2013 Aug 20;110(34):13863-8. doi: 10.1073/pnas.1304529110. Epub 2013 Aug 5.
Mouse bone marrow-derived Lin(-)-Sca-1(+) endothelial progenitor cell (EPC) has pluripotent abilities such as supporting neovascularization. Vascular endothelial growth factor (VEGF) receptor 1 (VEGFR1) (Flt1) recognizes various VEGF isoforms and is critically implicated in a wide range of physiological and pathological settings, including vasculogenesis. Mouse EPC expresses two isoforms of VEGFR1: mFlt1, which transmits ligand-induced signals; and sFlt1, which acts as a negative regulator by sequestering ligands of VEGF receptors. How the relative levels of mFlt1 and sFlt1 are regulated is not yet clear. We report here that tumor necrosis factor superfamily 15 (TNFSF15) (also known as VEGI or TL1A), an endothelial cell-secreted cytokine, simultaneously promotes mFlt1 degradation and up-regulates sFlt1 expression in EPC, giving rise to disruption of VEGF- or PlGF-induced activation of eNOS and MAPK p38 and effective inhibition of VEGF-driven, EPC-supported vasculogenesis in a murine Matrigel implant model. TNFSF15 treatment of EPC cultures facilitates Akt deactivation-dependent, ubiquitin-assisted degradation of mFlt1 and stimulates sFlt1 expression by activating the PKC, Src, and Erk1/2 signaling pathway. Additionally, TNFSF15 promotes alternative splicing of the Flt1 gene in favor of sFlt1 production by down-regulating nuclear protein Jumonji domain-containing protein 6 (Jmjd6), thus alleviating Jmjd6-inhibited sFlt1 expression. These findings indicate that TNFSF15 is a key component of a molecular mechanism that negatively modulates EPC-supported vasculogenesis through regulation of the relative levels of mFlt1 and sFlt1 in EPC.
小鼠骨髓来源的 Lin(-)-Sca-1(+)内皮祖细胞（EPC）具有支持新血管生成的多能能力。血管内皮生长因子受体 1（VEGFR1）（Flt1）识别各种 VEGF 同工型，在广泛的生理和病理环境中都具有重要作用，包括血管生成。小鼠 EPC 表达两种 VEGFR1 同工型：mFlt1，传递配体诱导的信号；和 sFlt1，通过隔离 VEGF 受体的配体起负调节作用。mFlt1 和 sFlt1 的相对水平如何调节尚不清楚。我们在这里报告，肿瘤坏死因子超家族 15（TNFSF15）（也称为 VEGI 或 TL1A），一种内皮细胞分泌的细胞因子，同时促进 EPC 中 mFlt1 的降解和 sFlt1 的表达上调，导致 VEGF 或 PlGF 诱导的 eNOS 和 MAPK p38 的激活中断，并在小鼠 Matrigel 植入模型中有效抑制 VEGF 驱动的、EPC 支持的血管生成。TNFSF15 处理 EPC 培养物促进 Akt 失活依赖性、泛素辅助的 mFlt1 降解，并通过激活 PKC、Src 和 Erk1/2 信号通路刺激 sFlt1 表达。此外，TNFSF15 通过下调核蛋白 Jumonji 结构域包含蛋白 6（Jmjd6）促进 Flt1 基因的选择性剪接，有利于 sFlt1 的产生，从而减轻 Jmjd6 抑制的 sFlt1 表达。这些发现表明，TNFSF15 是一个关键组成部分，通过调节 EPC 中 mFlt1 和 sFlt1 的相对水平，负调控 EPC 支持的血管生成的分子机制。
