Department of Developmental Genetics, Max Planck Institute for Heart and Lung Research, 61231 Bad Nauheim, Germany.
Nat Commun. 2017 May 19;8:15492. doi: 10.1038/ncomms15492.
Macrophages are known to interact with endothelial cells during developmental and pathological angiogenesis but the molecular mechanisms modulating these interactions remain unclear. Here, we show a role for the Hif-1α transcription factor in this cellular communication. We generated hif-1aa;hif-1ab double mutants in zebrafish, hereafter referred to as hif-1α mutants, and find that they exhibit impaired macrophage mobilization from the aorta-gonad-mesonephros (AGM) region as well as angiogenic defects and defective vascular repair. Importantly, macrophage ablation is sufficient to recapitulate the vascular phenotypes observed in hif-1α mutants, revealing for the first time a macrophage-dependent angiogenic process during development. Further substantiating our observations of vascular repair, we find that most macrophages closely associated with ruptured blood vessels are Tnfα-positive, a key feature of classically activated macrophages. Altogether, our data provide genetic evidence that Hif-1α regulates interactions between macrophages and endothelial cells starting with the mobilization of macrophages from the AGM.
巨噬细胞在发育和病理性血管生成过程中已知与内皮细胞相互作用，但调节这些相互作用的分子机制尚不清楚。在这里，我们展示了 Hif-1α 转录因子在这种细胞通讯中的作用。我们在斑马鱼中生成了 hif-1aa;hif-1ab 双突变体，此后称为 hif-1α 突变体，发现它们表现出从主动脉性腺中肾（AGM）区域动员巨噬细胞的能力受损，以及血管生成缺陷和血管修复缺陷。重要的是，巨噬细胞消融足以重现 hif-1α 突变体中观察到的血管表型，首次揭示了发育过程中巨噬细胞依赖性血管生成过程。进一步证实我们对血管修复的观察结果，我们发现与破裂血管密切相关的大多数巨噬细胞都是 Tnfα 阳性的，这是经典活化巨噬细胞的一个关键特征。总之，我们的数据提供了遗传证据，表明 Hif-1α 调节巨噬细胞和内皮细胞之间的相互作用，从 AGM 中巨噬细胞的动员开始。
