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.

血管性认知障碍和痴呆 (VCID) 是仅次于阿尔茨海默病 (AD) 的第二种最常见的痴呆形式。目前，对 VCID 演变和进展的机制见解仍然难以捉摸。白质变化代表不变的特征。令人信服的临床神经影像学和病理学证据表明白质变化与神经变性之间存在联系。我们之前的研究在非常年幼的小鼠中发现了内皮一氧化氮 (eNOS) 部分缺乏症的低灌注病变，与临床前 AD 患者中发现的那些低灌注区域精确匹配。白质束特别容易受到慢性灌注不足引起的血管损伤的影响。使用免疫组织化学，我们检测到中年 eNOS 缺陷小鼠的严重脱髓鞘。脱髓鞘区域局限于皮质和皮质下区域，包括胼胝体和海马体。脱髓鞘的强度与步态和联想识别记忆表现的行为缺陷相关。通过伊文思蓝血管造影，我们检测到血脑屏障 (BBB) 渗漏是影响 eNOS 缺陷小鼠额叶和顶叶皮质的另一种早期病理变化。向年轻和中年 eNOS 缺陷小鼠提供的硝酸钠强化饮用水完全防止了非灌注、BBB 渗漏和白质病理，表明受损的内皮衍生 NO 信号可能导致了这些病理事件。此外，全基因组转录组学分析揭示了在年轻的 eNOS 缺陷小鼠的白质中选择性地与线粒体呼吸通路最相关的改变基因簇。使用 eNOS 缺陷小鼠，我们将 BBB 分解和低灌注确定为两个最早的病理事件，由血管 NO 信号不足引起。我们推测受损的 BBB 和轻度慢性低灌注会引发血管损伤，以及氧化应激和星形胶质细胞增生，从而解释 eNOS 缺陷小鼠模型中的白质病理变化。我们得出结论，eNOS 缺陷小鼠代表了一种理想的自发进化模型，用于研究导致白质变化的最早事件，