Oulu Center for Cell-Matrix Research, Faculty of Biochemistry and Molecular Medicine, University of Oulu, Oulu, Finland.
Biocenter Oulu, University of Oulu, Oulu, Finland.
Elife. 2018 Nov 16;7:e37776. doi: 10.7554/eLife.37776.
The maintenance of fluid homeostasis is necessary for function of the neural retina; however, little is known about the significance of potential fluid management mechanisms. Here, we investigated angiopoietin-4 (Angpt4, also known as Ang3), a poorly characterized ligand for endothelial receptor tyrosine kinase Tie2, in mouse retina model. By using genetic reporter, fate mapping, and in situ hybridization, we found expression in a specific sub-population of astrocytes at the site where venous morphogenesis occurs and that lower oxygen tension, which distinguishes peripheral and venous locations, enhances Angpt4 expression. Correlating with its spatiotemporal expression, deletion of resulted in defective venous development causing impaired venous drainage and defects in neuronal cells. In vitro characterization of angiopoietin-4 proteins revealed both ligand-specific and redundant functions among the angiopoietins. Our study identifies Angpt4 as the first growth factor for venous-specific development and its importance in venous remodeling, retinal fluid clearance and neuronal function.
维持液体动态平衡对于神经视网膜的功能至关重要；然而，对于潜在的液体管理机制的意义知之甚少。在这里，我们研究了血管生成素-4（Angpt4，也称为 Ang3），它是一种对内皮受体酪氨酸激酶 Tie2 具有特征性的配体，在小鼠视网膜模型中。通过使用遗传报告、命运图谱和原位杂交，我们发现它在静脉形态发生发生的部位的特定星形胶质细胞亚群中表达，并且低氧张力（区分外围和静脉位置）增强了 Angpt4 的表达。与其时空表达相关，缺失导致静脉发育不良，导致静脉引流受损和神经元细胞缺陷。对血管生成素-4 蛋白的体外特性分析表明，血管生成素在配体特异性和冗余功能方面具有多样性。我们的研究将 Angpt4 确定为第一个具有静脉特异性发育功能的生长因子，以及其在静脉重塑、视网膜液体清除和神经元功能中的重要性。
