Han Chul, Lang Michael J, Nguyen Candice L, Luna Melendez Ernesto, Mehta Shwetal, Turner Gregory H, Lawton Michael T, Oh S Paul
1Barrow Aneurysm and AVM Research Center, Department of Translational Neuroscience, Barrow Neurological Institute, St. Joseph's Hospital and Medical Center, Phoenix.
Departments of2Neurosurgery and.
J Neurosurg. 2021 Nov 5;137(1):163-174. doi: 10.3171/2021.6.JNS21717. Print 2022 Jul 1.
Hereditary hemorrhagic telangiectasia is the only condition associated with multiple inherited brain arteriovenous malformations (AVMs). Therefore, a mouse model was developed with a genetics-based approach that conditionally deleted the causative activin receptor-like kinase 1 (Acvrl1 or Alk1) gene. Radiographic and histopathological findings were correlated, and AVM stability and hemorrhagic behavior over time were examined.
Alk1-floxed mice were crossed with deleter mice to generate offspring in which both copies of the Alk1 gene were deleted by Tagln-Cre to form brain AVMs in the mice. AVMs were characterized using MRI, MRA, and DSA. Brain AVMs were characterized histopathologically with latex dye perfusion, immunofluorescence, and Prussian blue staining.
Brains of 55 Tagln-Cre+;Alk12f/2f mutant mice were categorized into three groups: no detectable vascular lesions (group 1; 23 of 55, 42%), arteriovenous fistulas (AVFs) with no nidus (group 2; 10 of 55, 18%), and nidal AVMs (group 3; 22 of 55, 40%). Microhemorrhage was observed on MRI or MRA in 11 AVMs (50%). AVMs had the angiographic hallmarks of early nidus opacification, a tangle of arteries and dilated draining veins, and rapid shunting of blood flow. Latex dye perfusion confirmed arteriovenous shunting in all AVMs and AVFs. Microhemorrhages were detected adjacent to AVFs and AVMs, visualized by iron deposition, Prussian blue staining, and macrophage infiltration using CD68 immunostaining. Brain AVMs were stable on serial MRI and MRA in group 3 mice (mean age at initial imaging 2.9 months; mean age at last imaging 9.5 months).
Approximately 40% of transgenic mice satisfied the requirements of a stable experimental AVM model by replicating nidal anatomy, arteriovenous hemodynamics, and microhemorrhagic behavior. Transgenic mice with AVFs had a recognizable phenotype of hereditary hemorrhagic telangiectasia but were less suitable for experimental modeling. AVM pathogenesis can be understood as the combination of conditional Alk1 gene deletion during embryogenesis and angiogenesis that is hyperactive in developing and newborn mice, which translates to a congenital origin in most patients but an acquired condition in patients with a confluence of genetic and angiogenic events later in life. This study offers a novel experimental brain AVM model for future studies of AVM pathophysiology, growth, rupture, and therapeutic regression.
遗传性出血性毛细血管扩张症是唯一与多发性遗传性脑动静脉畸形（AVM）相关的疾病。因此，采用基于遗传学的方法构建了一种小鼠模型，该模型有条件地删除了致病的激活素受体样激酶1（Acvrl1或Alk1）基因。将影像学和组织病理学结果进行关联，并研究AVM随时间的稳定性和出血行为。
将Alk1基因条件性敲除小鼠与删除小鼠杂交，产生后代，其中Alk1基因的两个拷贝通过Tagln-Cre被删除，从而在小鼠中形成脑AVM。使用MRI、MRA和DSA对AVM进行特征描述。通过乳胶染料灌注、免疫荧光和普鲁士蓝染色对脑AVM进行组织病理学特征描述。
55只Tagln-Cre+;Alk12f/2f突变小鼠的脑部分为三组：未检测到血管病变（第1组；55只中的23只，42%）、无病灶的动静脉瘘（AVF）（第2组；55只中的10只，18%）和有病灶的AVM（第3组；55只中的22只，40%）。11个AVM（50%）在MRI或MRA上观察到微出血。AVM具有早期病灶显影、动脉缠结和引流静脉扩张以及血流快速分流的血管造影特征。乳胶染料灌注证实所有AVM和AVF均存在动静脉分流。在AVF和AVM附近检测到微出血，通过铁沉积、普鲁士蓝染色以及使用CD68免疫染色观察巨噬细胞浸润来显示。第3组小鼠的脑AVM在系列MRI和MRA上表现稳定（初始成像时的平均年龄为2.9个月；末次成像时的平均年龄为9.5个月）。
大约40%的转基因小鼠通过复制病灶解剖结构、动静脉血流动力学和微出血行为，满足了稳定的实验性AVM模型的要求。患有AVF的转基因小鼠具有可识别的遗传性出血性毛细血管扩张症表型，但不太适合用于实验建模。AVM的发病机制可理解为胚胎发育过程中Alk1基因的条件性缺失与发育中和新生小鼠中过度活跃的血管生成相结合，这在大多数患者中转化为先天性起源，但在生命后期发生遗传和血管生成事件汇合的患者中则为后天性疾病。本研究为未来AVM病理生理学、生长、破裂和治疗消退的研究提供了一种新型的实验性脑AVM模型。
