Mechanisms underlying arteriovenous malformations (AVMs) are poorly understood. Using mice with endothelial cell (EC) expression of constitutively active Notch4 (Notch4* EC ), we show decreased arteriolar tone in vivo during brain AVM initiation. Reduced vascular tone is a primary effect of Notch4* EC , as isolated pial arteries from asymptomatic mice exhibited reduced pressure-induced arterial tone ex vivo. The nitric oxide (NO) synthase (NOS) inhibitor NG-nitro- l -arginine (L-NNA) corrected vascular tone defects in both assays. L-NNA treatment or endothelial NOS ( eNOS ) gene deletion, either globally or specifically in ECs, attenuated AVM initiation, assessed by decreased AVM diameter and delayed time to moribund. Administering nitroxide antioxidant 4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl also attenuated AVM initiation. Increased NOS-dependent production of hydrogen peroxide, but not NO, superoxide, or peroxynitrite was detected in isolated Notch4* EC brain vessels during AVM initiation. Our data suggest that eNOS is involved in Notch4* EC -mediated AVM formation by up-regulating hydrogen peroxide and reducing vascular tone, thereby permitting AVM initiation and progression.

中文翻译：

---

一氧化氮合酶和动脉张力降低导致动静脉畸形

人们对动静脉畸形（AVM）的机制知之甚少。使用内皮细胞 (EC) 表达组成型活性 Notch4 的小鼠 (Notch4*欧共体），我们发现在脑 AVM 启动期间体内小动脉张力降低。降低血管张力是 Notch4* 的主要作用欧共体，因为从无症状小鼠身上分离出的软脑膜动脉表现出离体压力诱导的动脉张力降低。一氧化氮 (NO) 合酶 (NOS) 抑制剂 NG-硝基-我-精氨酸（L-NNA）纠正了两种测定中的血管张力缺陷。L-NNA 治疗或内皮 NOS（内皮型一氧化氮合酶）基因缺失，无论是整体还是在 EC 中，都会减弱 AVM 的启动，通过 AVM 直径的减小和垂死时间的延迟来评估。施用硝基氧抗氧化剂 4-羟基-2,2,6,6-四甲基哌啶-1-氧基也能减弱 AVM 的引发。在分离的 Notch4 中检测到 NOS 依赖性过氧化氢生成增加，但未检测到 NO、超氧化物或过氧亚硝酸盐*欧共体AVM 启动期间的脑血管。我们的数据表明 eNOS 参与 Notch4*欧共体-通过上调过氧化氢和降低血管张力介导AVM形成，从而允许AVM启动和进展。