Localized conditional induction of brain arteriovenous malformations in a mouse model of hereditary hemorrhagic telangiectasia,Angiogenesis

当前位置： X-MOL 学术 › Angiogenesis › 论文详情

Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)

Localized conditional induction of brain arteriovenous malformations in a mouse model of hereditary hemorrhagic telangiectasia
Angiogenesis ( IF 9.2 ) Pub Date : 2023-05-23 , DOI: 10.1007/s10456-023-09881-w
Lea Scherschinski _{1,

2,

3} , Chul Han ₁ , Yong Hwan Kim ₁ , Ethan A Winkler _{1,

2} , Joshua S Catapano ₂ , Tyler D Schriber ₁ , Peter Vajkoczy ₃ , Michael T Lawton _{1,

2} , S Paul Oh ₁

Affiliation

Background

Longitudinal mouse models of brain arteriovenous malformations (AVMs) are crucial for developing novel therapeutics and pathobiological mechanism discovery underlying brain AVM progression and rupture. The sustainability of existing mouse models is limited by ubiquitous Cre activation, which is associated with lethal hemorrhages resulting from AVM formation in visceral organs. To overcome this condition, we developed a novel experimental mouse model of hereditary hemorrhagic telangiectasia (HHT) with CreER-mediated specific, localized induction of brain AVMs.

Methods

Hydroxytamoxifen (4-OHT) was stereotactically delivered into the striatum, parietal cortex, or cerebellum of R26^CreER; Alk1^2f/2f (Alk1-iKO) littermates. Mice were evaluated for vascular malformations with latex dye perfusion and 3D time-of-flight magnetic resonance angiography (MRA). Immunofluorescence and Prussian blue staining were performed for vascular lesion characterization.

Results

Our model produced two types of brain vascular malformations, including nidal AVMs (88%, 38/43) and arteriovenous fistulas (12%, 5/43), with an overall frequency of 73% (43/59). By performing stereotaxic injection of 4-OHT targeting different brain regions, Alk1-iKO mice developed vascular malformations in the striatum (73%, 22/30), in the parietal cortex (76%, 13/17), and in the cerebellum (67%, 8/12). Identical application of the stereotaxic injection protocol in reporter mice confirmed localized Cre activity near the injection site. The 4-week mortality was 3% (2/61). Seven mice were studied longitudinally for a mean (SD; range) duration of 7.2 (3; 2.3−9.5) months and demonstrated nidal stability on sequential MRA. The brain AVMs displayed microhemorrhages and diffuse immune cell invasion.

Conclusions

We present the first HHT mouse model of brain AVMs that produces localized AVMs in the brain. The mouse lesions closely resemble the human lesions for complex nidal angioarchitecture, arteriovenous shunts, microhemorrhages, and inflammation. The model’s longitudinal robustness is a powerful discovery resource to advance our pathomechanistic understanding of brain AVMs and identify novel therapeutic targets.

中文翻译：

遗传性出血性毛细血管扩张小鼠模型脑动静脉畸形的局部条件诱导

背景

脑动静脉畸形（AVM）的纵向小鼠模型对于开发新的治疗方法和发现脑动静脉畸形进展和破裂的病理生物学机制至关重要。现有小鼠模型的可持续性受到普遍存在的 Cre 激活的限制，Cre 激活与内脏器官中 AVM 形成导致的致命性出血有关。为了克服这种情况，我们开发了一种新的遗传性出血性毛细血管扩张症 (HHT) 实验小鼠模型，通过 CreER 介导的脑 AVM 特异性、局部诱导。

方法

^{羟基他莫昔芬 (4-OHT) 被立体定向递送至 R26 CreER}的纹状体、顶叶皮质或小脑；Alk1 ^2f/2f ( Alk1 -iKO) 同窝仔。通过乳胶染料灌注和 3D 飞行时间磁共振血管造影 (MRA) 评估小鼠的血管畸形。进行免疫荧光和普鲁士蓝染色来表征血管病变。

结果

我们的模型产生了两种类型的脑血管畸形，包括巢状 AVM（88%，38/43）和动静脉瘘（12%，5/43），总频率为 73%（43/59）。通过针对不同大脑区域进行 4-OHT 立体定位注射，Alk1 -iKO 小鼠在纹状体 (73%, 22/30)、顶叶皮层 (76%, 13/17) 和小脑 (76%, 13/17) 中出现血管畸形。 67%，8/12）。在报告小鼠中同样应用立体定位注射方案证实了注射部位附近的局部 Cre 活性。 4 周死亡率为 3% (2/61)。对七只小鼠进行了平均（SD；范围）持续时间为 7.2（3；2.3−9.5）个月的纵向研究，并在序贯 MRA 上证明了 Nidal 稳定性。脑动静脉畸形显示微出血和弥漫性免疫细胞侵袭。