White matter damage as a consequence of vascular dysfunction in a spontaneous mouse model of chronic mild chronic hypoperfusion with eNOS deficiency.
White matter damage as a consequence of vascular dysfunction in a spontaneous mouse model of chronic mild chronic hypoperfusion with eNOS deficiency.
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DOI：
10.1038/s41380-022-01701-9
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发表时间：
2022-11
影响因子：
11
通讯作者：
Liao, Francesca-Fang
中科院分区：
文献类型：
--
作者：
Chen, Xingyong;Chen, Ling;Lin, Geng;Wang, Zhengjun;Kodali, Mahesh C.;Li, Mingqi;Chen, Huimin;Lebovitz, Sarah G.;Ortyl, Tyler C.;Li, Lexiao;Ismael, Saifudeen;Singh, Purnima;Malik, Kafait U.;Ishrat, Tauheed;Zhou, Fu-Ming;Zheng, Wei;Liao, Francesca-Fang
血管性认知障碍和痴呆（VCID）是仅次于阿尔茨海默病（AD）的第二常见的痴呆形式。目前，对VCID的进化和进展的机制见解仍然难以捉摸。白质变化是一个不变的特征。令人信服的临床神经影像学和病理证据表明白质变化与神经变性之间存在联系。我们之前的研究发现，在很小的时候，内皮性一氧化氮（eNOS）部分缺乏的小鼠中发现了灌注不足的病变，与临床前AD患者中发现的那些灌注不足的区域精确匹配。白质束特别容易受到慢性灌注不足引起的血管损伤。利用免疫组化技术，我们检测到了中年enos缺陷小鼠的严重脱髓鞘。脱髓鞘区局限于皮层和皮层下区域，包括胼胝体和海马。脱髓鞘强度与步态行为缺陷和联想识别记忆表现相关。通过Evans蓝血管造影，我们发现血脑屏障（BBB）渗漏是影响enos缺陷小鼠额叶和顶叶皮层的另一种早期病理改变。提供硝酸钠强化饮用水给中青年enos缺陷小鼠完全阻止非灌注、血脑屏障渗漏和白质病理，表明内皮来源的NO信号受损可能导致了这些病理事件。此外，全基因组转录组学分析显示，在年轻的enos缺陷小鼠的白质中，与线粒体呼吸途径选择性相关的基因簇发生了改变。使用enos缺陷小鼠，我们确定血脑屏障破裂和灌注不足是两个最早的病理事件，由血管NO信号传导不足引起。我们推测血脑屏障受损和轻度慢性灌注不足引发血管损伤，以及氧化应激和星形胶质细胞增生，这是导致enos缺陷小鼠模型白质病理改变的原因。我们得出结论，enos缺陷小鼠是研究导致白质变化的早期事件的理想自发进化模型，这将有助于未来候选药物的治疗测试以及针对导致VCID和AD的新型/特异性血管机制。
Vascular cognitive impairment and dementia (VCID) is the second most common form of dementia after Alzheimer’s disease (AD). Currently, the mechanistic insights into the evolution and progression of VCID remain elusive. White matter change represents an invariant feature. Compelling clinical neuroimaging and pathological evidence suggest a link between white matter changes and neurodegeneration. Our prior study detected hypoperfused lesions in mice with partial deficiency of endothelial nitric oxide (eNOS) at very young age, precisely matching to those hypoperfused areas identified in preclinical AD patients. White matter tracts are particularly susceptible to the vascular damage induced by chronic hypoperfusion. Using immunohistochemistry, we detected severe demyelination in the middle-aged eNOS-deficient mice. The demyelinated areas were confined to cortical and subcortical areas including the corpus callosum and hippocampus. The intensity of demyelination correlated with behavioral deficits of gait and associative recognition memory performances. By Evans blue angiography, we detected blood–brain barrier (BBB) leakage as another early pathological change affecting frontal and parietal cortex in eNOS-deficient mice. Sodium nitrate fortified drinking water provided to young and middle-aged eNOS-deficient mice completely prevented non-perfusion, BBB leakage, and white matter pathology, indicating that impaired endothelium-derived NO signaling may have caused these pathological events. Furthermore, genome-wide transcriptomic analysis revealed altered gene clusters most related to mitochondrial respiratory pathways selectively in the white matter of young eNOS-deficient mice. Using eNOS-deficient mice, we identified BBB breakdown and hypoperfusion as the two earliest pathological events, resulting from insufficient vascular NO signaling. We speculate that the compromised BBB and mild chronic hypoperfusion trigger vascular damage, along with oxidative stress and astrogliosis, accounting for the white matter pathological changes in the eNOS-deficient mouse model. We conclude that eNOS-deficient mice represent an ideal spontaneous evolving model for studying the earliest events leading to white matter changes, which will be instrumental to future therapeutic testing of drug candidates and for targeting novel/specific vascular mechanisms contributing to VCID and AD.
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影响因子：
--
作者：
Dickstein, Dara L.;Walsh, Jessica;Brautigam, Hannah;Stockton, Steven D., Jr.;Gandy, Samuel;Hof, Patrick R.
通讯作者：
Hof, Patrick R.
影响因子：
37.8
作者：
Duplain, H;Burcelin, R;Scherrer, U
通讯作者：
Scherrer, U
DOI：
10.1073/pnas.1008872107
发表时间：
2010-10-12
影响因子：
11.1
作者：
Carlstrom, Mattias;Larsen, Filip J.;Lundberg, Jon O.
通讯作者：
Lundberg, Jon O.
影响因子：
3.9
作者：
Hariharan, Ashwini;Jing, Yu;Liu, Ping
通讯作者：
Liu, Ping
血管认知障碍的翻译模型：包括较大物种的综述。
影响因子：
9.3
作者：
Hainsworth AH;Allan SM;Boltze J;Cunningham C;Farris C;Head E;Ihara M;Isaacs JD;Kalaria RN;Lesnik Oberstein SA;Moss MB;Nitzsche B;Rosenberg GA;Rutten JW;Salkovic-Petrisic M;Troen AM
通讯作者：
Troen AM