Bower Neil I, Vogrin Adam J, Le Guen Ludovic, Chen Huijun, Stacker Steven A, Achen Marc G, Hogan Benjamin M
Division of Genomics of Development and Disease, Institute for Molecular Bioscience, The University of Queensland, St Lucia, Brisbane, Queensland 4072, Australia.
Tumour Angiogenesis and Microenvironment Program, Peter MacCallum Cancer Centre, Melbourne, Victoria 3000, Australia.
Development. 2017 Feb 1;144(3):507-518. doi: 10.1242/dev.146969. Epub 2017 Jan 13.
Vascular endothelial growth factors (VEGFs) control angiogenesis and lymphangiogenesis during development and in pathological conditions. In the zebrafish trunk, Vegfa controls the formation of intersegmental arteries by primary angiogenesis and Vegfc is essential for secondary angiogenesis, giving rise to veins and lymphatics. Vegfd has been largely thought of as dispensable for vascular development in vertebrates. Here, we generated a zebrafish vegfd mutant by genome editing. vegfd mutants display significant defects in facial lymphangiogenesis independent of vegfc function. Strikingly, we find that vegfc and vegfd cooperatively control lymphangiogenesis throughout the embryo, including during the formation of the trunk lymphatic vasculature. Interestingly, we find that vegfd and vegfc also redundantly drive artery hyperbranching phenotypes observed upon depletion of Flt1 or Dll4. Epistasis and biochemical binding assays suggest that, during primary angiogenesis, Vegfd influences these phenotypes through Kdr (Vegfr2) rather than Flt4 (Vegfr3). These data demonstrate that, rather than being dispensable during development, Vegfd plays context-specific indispensable and also compensatory roles during both blood vessel angiogenesis and lymphangiogenesis.
血管内皮生长因子（VEGFs）在发育过程和病理状态下控制血管生成和淋巴管生成。在斑马鱼躯干中，Vegfa通过初级血管生成控制节间动脉的形成，而Vegfc对次级血管生成至关重要，可形成静脉和淋巴管。Vegfd在很大程度上被认为对脊椎动物的血管发育无关紧要。在此，我们通过基因组编辑产生了斑马鱼vegfd突变体。vegfd突变体在面部淋巴管生成中表现出明显缺陷，且与vegfc功能无关。令人惊讶的是，我们发现vegfc和vegfd协同控制整个胚胎的淋巴管生成，包括躯干淋巴管系统的形成过程。有趣的是，我们发现vegfd和vegfc在Flt1或Dll4缺失时也会冗余地驱动动脉过度分支表型。上位性和生化结合试验表明，在初级血管生成过程中，Vegfd通过Kdr（Vegfr2）而非Flt4（Vegfr3）影响这些表型。这些数据表明，Vegfd在发育过程中并非无关紧要，而是在血管生成和淋巴管生成过程中发挥着特定背景下不可或缺的以及补偿性的作用。
