The molecular mechanisms of angiogenesis have been intensely studied, but many genes that control endothelial behavior and fate still need to be described. Here, we characterize the role of Apold1 (Apolipoprotein L domain containing 1) in angiogenesis in vivo and in vitro. Single-cell analyses reveal that - across tissues - the expression of Apold1 is restricted to the vasculature and that Apold1 expression in endothelial cells (ECs) is highly sensitive to environmental factors. Using Apold1^−/− mice, we find that Apold1 is dispensable for development and does not affect postnatal retinal angiogenesis nor alters the vascular network in adult brain and muscle. However, when exposed to ischemic conditions following photothrombotic stroke as well as femoral artery ligation, Apold1^−/− mice display dramatic impairments in recovery and revascularization. We also find that human tumor endothelial cells express strikingly higher levels of Apold1 and that Apold1 deletion in mice stunts the growth of subcutaneous B16 melanoma tumors, which have smaller and poorly perfused vessels. Mechanistically, Apold1 is activated in ECs upon growth factor stimulation as well as in hypoxia, and Apold1 intrinsically controls EC proliferation but not migration. Our data demonstrate that Apold1 is a key regulator of angiogenesis in pathological settings, whereas it does not affect developmental angiogenesis, thus making it a promising candidate for clinical investigation.

血管生成的分子机制已被深入研究，但许多控制内皮行为和命运的基因仍需要描述。在这里，我们描述了Apold1（含有载脂蛋白 L 结构域 1）在体内和体外血管生成中的作用。单细胞分析表明，在整个组织中， Apold1的表达仅限于脉管系统，并且内皮细胞 (EC) 中的Apold1表达对环境因素高度敏感。使用Apold1 ^−/−小鼠，我们发现Apold1对于发育来说是必需的，并且不会影响出生后视网膜血管生成，也不会改变成年大脑和肌肉中的血管网络。然而，当暴露于光血栓性中风以及股动脉结扎后的缺血条件下时，Apold1 ^−/−小鼠在恢复和血运重建方面表现出显着的损伤。我们还发现，人类肿瘤内皮细胞表达的Apold1水平显着升高，而小鼠中的Apold1缺失会阻碍皮下 B16 黑色素瘤的生长，因为皮下 B16 黑色素瘤的血管较小且灌注不良。从机制上讲，Apold1在生长因子刺激和缺氧时在 EC 中被激活，并且Apold1本质上控制 EC 增殖，但不控制迁移。我们的数据表明Apold1是病理环境中血管生成的关键调节因子，但它不影响发育性血管生成，因此使其成为临床研究的有希望的候选者。