Gradual Carotid Artery Stenosis in Mice Closely Replicates Hypoperfusive Vascular Dementia in Humans.
Gradual Carotid Artery Stenosis in Mice Closely Replicates Hypoperfusive Vascular Dementia in Humans.
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DOI：
10.1161/jaha.115.002757
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发表时间：
2016-02-22
影响因子：
5.4
通讯作者：
Ihara M
中科院分区：
文献类型：
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作者：
Hattori Y;Enmi J;Iguchi S;Saito S;Yamamoto Y;Tsuji M;Nagatsuka K;Kalaria RN;Iida H;Ihara M
现有的血管性认知障碍（VCI）啮齿动物模型显示脑血流量（CBF）的突然变化，并且不能可靠地复制VCI的临床发病机制。因此，我们的目的是开发一种VCI小鼠模型，其中CBF逐渐减少，随后进行性运动和认知障碍，手术干预后。通过使用内径为0.75 mm的Ameroid收缩器血管收缩装置，对成年C57 BL/6 J雄性小鼠进行渐进式颈总动脉狭窄（GCAS）手术。GCAS后28天，颈总动脉在Ameroid缩窄器逐渐收缩后逐渐变窄，随后由于图尼卡内膜中的平滑肌细胞增殖和巨噬细胞浸润导致79.3%的面积狭窄。28天生存率为91%。动脉自旋标记显示皮质和皮质下CBF（与术前值的比率）在28天内分别逐渐和连续减少至54.6%和51.5%。然而，磁共振血管造影显示软脑膜动脉侧支血流信号增加。32天时，在白色物质中发现星形胶质细胞和小胶质细胞稀疏和增殖，少突胶质细胞丢失。仅在25%的GCAS小鼠中观察到海马神经元损失，这与Morris水迷宫试验中没有异常一致。旋转杆测试显示运动障碍，Y迷宫测试显示工作记忆缺陷。GCAS模型在28天内成功地产生了逐渐和连续的CBF减少，复制了与脑灌注不足相关的关键组织学、放射学和行为学特征，导致VCI。
Existing rodent models of vascular cognitive impairment (VCI) show abrupt changes in cerebral blood flow (CBF) and do not reliably replicate the clinical pathogenesis of VCI. We therefore aimed to develop a mouse model of VCI where CBF is gradually reduced, followed by subsequent progressive motor and cognitive impairment, after surgical intervention. Adult C57BL/6J male mice were subjected to gradual common carotid artery stenosis (GCAS) surgery by using an ameroid constrictor vessel‐constricting device with an inner diameter of 0.75 mm. The common carotid arteries narrowed gradually after gradual constriction of ameroid constrictors over 28 days after GCAS, with subsequent 79.3% area stenosis as a result of smooth muscle cell proliferation and macrophage infiltration in the tunica intima. The 28‐day survival rate was 91%. Arterial spin labeling demonstrated gradual and continuous reduction of cortical and subcortical CBF (ratio to the preoperative value) to 54.6% and 51.5%, respectively, over 28 days. However, magnetic resonance angiography showed increment of collateral flow signals in the leptomeningeal artery. Rarefaction and proliferation of astrocytes and microglia, with loss of oligodendrocytes, were found in the white matter at 32 days. Hippocampal neuronal loss was observed in only 25% of GCAS mice, consistent with lack of abnormalities in the Morris water maze test. The rotarod test showed motor impairment, and the Y‐maze test showed working memory deficits. The GCAS model successfully generated gradual and continuous CBF reduction over 28 days, with replication of key histological, radiological, and behavioral features associated with cerebral hypoperfusion leading to VCI.