Aims Arteriovenous malformations (AVMs), a disorder characterized by direct shunts between arteries and veins, are associated with genetic mutations. However, the mechanisms leading to AV shunt formation and how shunts can be reverted are poorly understood. Methods and results Here, we report that oxygen-induced retinopathy (OIR) protocol leads to the consistent and stereotypical formation of AV shunts in non-genetically altered mice. OIR-induced AV shunts show all the canonical markers of AVMs. Genetic and pharmacological interventions demonstrated that changes in the volume of venous endothelial cells (EC)—hypertrophic venous cells—are the initiating step promoting AV shunt formation, whilst EC proliferation or migration played minor roles. Inhibition of the mTOR pathway prevents pathological increases in EC volume and significantly reduces the formation of AV shunts. Importantly, we demonstrate that ALK1 signalling cell-autonomously regulates EC volume in pro-angiogenic conditions, establishing a link with hereditary haemorrhagic telangiectasia-related AVMs. Finally, we demonstrate that a combination of EC volume control and EC migration is associated with the regression of AV shunts. Conclusion Our findings highlight that an increase in the EC volume is the key mechanism driving the initial stages of AV shunt formation, leading to asymmetric capillary diameters. Based on our results, we propose a coherent and unifying timeline leading to the fast conversion of a capillary vessel into an AV shunt. Our data advocate for further investigation into the mechanisms regulating EC volume in health and disease as a way to identify therapeutic approaches to prevent and revert AVMs.

中文翻译：

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血管分流的非遗传模型揭示动静脉畸形形成和消退的细胞机制


目的 动静脉畸形 (AVM) 是一种以动脉和静脉之间直接分流为特征的疾病，与基因突变有关。然而，导致 AV 分流形成的机制以及分流如何恢复尚不清楚。方法和结果在这里，我们报告氧诱导视网膜病变（OIR）方案导致非基因改造小鼠中一致且典型的 AV 分流形成。 OIR 诱导的 AV 分流显示了 AVM 的所有典型标记。遗传和药理学干预表明，静脉内皮细胞（EC）（肥大的静脉细胞）体积的变化是促进 AV 分流形成的起始步骤，而 EC 增殖或迁移发挥次要作用。抑制 mTOR 通路可防止 EC 体积病理性增加，并显着减少 AV 分流的形成。重要的是，我们证明 ALK1 信号细胞在促血管生成条件下自主调节 EC 体积，与遗传性出血性毛细血管扩张相关的 AVM 建立联系。最后，我们证明 EC 容量控制和 EC 迁移的组合与 AV 分流的回归相关。结论 我们的研究结果强调，EC 体积的增加是驱动 AV 分流形成初始阶段的关键机制，导致毛细血管直径不对称。根据我们的结果，我们提出了一个连贯且统一的时间表，可将毛细血管快速转换为 AV 分流器。我们的数据主张进一步研究健康和疾病中 EC 体积的调节机制，以此确定预防和恢复 AVM 的治疗方法。