Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD 4072, Australia.
Diamantina Institute, Translational Research Institute, The University of Queensland, Brisbane, QLD 4072, Australia.
Dev Cell. 2017 Jan 23;40(2):123-136. doi: 10.1016/j.devcel.2016.12.017.
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.
血管生成负责胚胎发育过程中的组织血管化，以及在包括癌症和缺血在内的病理情况下。血管内皮生长因子 (VEGF) 通过与 VEGF 受体相互作用来诱导内皮细胞信号转导，从而调节血管生成。VEGF 在细胞外基质 (ECM) 中进行加工，但 ECM 对 VEGF 信号转导和血管生成的控制的复杂性还远未被理解。在正向遗传筛选中，我们在缺乏动脉和静脉 Vegf/Vegfr/Erk 信号的 tmem2 斑马鱼突变体中发现了血管生成缺陷。引人注目的是，tmem2 突变体显示出发育中的血管周围透明质酸 (HA) 增加。tmem2 突变体中的血管生成可以通过降解这种增加的 HA 来挽救，或者在发芽失败后恢复。此外，聚集的 HA 或 Vegfc 的过表达可以挽救 tmem2 突变体中的血管生成。基于这些数据以及 Tmem2 的已知结构，我们发现 Tmem2 通过调节 HA 周转来促进发育性血管生成过程中正常的 Vegf 信号转导。
