Tmem2 Regulates Embryonic Vegf Signaling by Controlling Hyaluronic Acid Turnover
Tmem2 Regulates Embryonic Vegf Signaling by Controlling Hyaluronic Acid Turnover
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DOI：
10.1016/j.devcel.2016.12.017
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发表时间：
2017-01-23
影响因子：
11.8
通讯作者：
Smith, Kelly A.
中科院分区：
文献类型：
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作者：
De Angelis, Jessica E.;Lagendijk, Anne K.;Smith, Kelly A.
血管生成负责在发育期间以及在包括癌症和缺血的病理学背景中的组织血管化。血管内皮生长因子（VEGF）通过VEGF受体诱导内皮细胞信号传导来调节血管生成。VEGF在细胞外基质（ECM）中加工，但ECM控制VEGF信号传导和血管生成的复杂性仍远未了解。在正向遗传筛选中，我们鉴定了缺乏动脉和静脉VEGF/Vegfr/Erk信号传导的tmem 2斑马鱼突变体中的血管生成缺陷。引人注目的是，tmem 2突变体在发育中的血管周围显示出增加的透明质酸（HA）。tmem 2突变体中的血管生成通过降解这种增加的HA而被拯救，或在发芽失败后恢复。此外，寡聚HA或Vegfc的过表达挽救了tmem 2突变体中的血管生成。基于这些数据，以及Tmem 2的已知结构，我们发现Tmem 2调节HA周转以促进发育血管生成期间的正常VEGF信号传导。
Angiogenesis is responsible for tissue vascularization during development, as well as in pathological contexts, including cancer and ischemia. Vascular endothelial growth factors (VEGFs) regulate angiogenesis by acting through VEGF receptors to induce endothelial cell signaling. VEGF is processed in the extracellular matrix (ECM), but the complexity of ECM control of VEGF signaling and angiogenesis remains far from understood. In a forward genetic screen, we identified angiogenesis defects in tmem2 zebrafish mutants that lack both arterial and venous Vegf/Vegfr/Erk signaling. Strikingly, tmem2 mutants display increased hyaluronic acid (HA) surrounding developing vessels. Angiogenesis in tmem2 mutants was rescued, or restored after failed sprouting, by degrading this increased HA. Furthermore, oligomerized HA or overexpression of Vegfc rescued angiogenesis in tmem2 mutants. Based on these data, and the known structure of Tmem2, we find that Tmem2 regulates HA turnover to promote normal Vegf signaling during developmental angiogenesis.