Department of Pharmacology, Addiction Science, Toxicology, University of Tennessee Health Science Center, College of Medicine, Memphis, Tennessee.
Department of Pharmacology, Addiction Science, Toxicology, University of Tennessee Health Science Center, College of Medicine, Memphis, Tennessee; Department of Histology and Embryology, Basic Medical University, China Medical University, Shenyang, China.
Am J Pathol. 2021 Nov;191(11):1932-1945. doi: 10.1016/j.ajpath.2021.02.022. Epub 2021 Mar 10.
Age-related cerebral small-vessel disease (CSVD) is a major cause of stroke and dementia. Despite a widespread acceptance of small-vessel arteriopathy, lacunar infarction, diffuse white matter injury, and cognitive impairment as four cardinal features of CSVD, a unifying pathologic mechanism of CSVD remains elusive. Herein, we introduce partial endothelial nitric oxide synthase (eNOS)-deficient mice as a model of age-dependent, spontaneous CSVD. These mice developed cerebral hypoperfusion and blood-brain barrier leakage at a young age, which progressively worsened with advanced age. Their brains exhibited elevated oxidative stress, astrogliosis, cerebral amyloid angiopathy, microbleeds, microinfarction, and white matter pathology. Partial eNOS-deficient mice developed gait disturbances at middle age, and hippocampus-dependent memory deficits at older ages. These mice also showed enhanced expression of bone morphogenetic protein 4 (BMP4) in brain pericytes before myelin loss and white matter pathology. Because BMP4 signaling not only promotes astrogliogenesis but also blocks oligodendrocyte differentiation, we posit that paracrine actions of BMP4, localized within the neurovascular unit, promote white matter disorganization and neurodegeneration. These observations point to BMP4 signaling pathway in the aging brain vasculature as a potential therapeutic target. Finally, because studies in partial eNOS-deficient mice corroborated recent clinical evidence that blood-brain barrier disruption is a primary cause of white matter pathology, the mechanism of impaired nitric oxide signaling-mediated CSVD warrants further investigation.
年龄相关性脑小血管病（CSVD）是中风和痴呆的主要原因。尽管小血管动脉病变、腔隙性梗死、弥漫性白质损伤和认知障碍被广泛认为是 CSVD 的四个主要特征，但 CSVD 的统一病理机制仍难以捉摸。在此，我们介绍部分内皮型一氧化氮合酶（eNOS）缺陷小鼠作为年龄依赖性自发性 CSVD 的模型。这些小鼠在年轻时就出现了脑灌注不足和血脑屏障渗漏，随着年龄的增长，情况逐渐恶化。它们的大脑表现出氧化应激、星形胶质细胞增生、脑淀粉样血管病、微出血、微梗死和白质病变增加。部分 eNOS 缺陷小鼠在中年时出现步态障碍，在老年时出现海马依赖性记忆缺陷。这些小鼠在髓鞘丢失和白质病变之前还表现出脑周细胞中骨形态发生蛋白 4（BMP4）的表达增强。由于 BMP4 信号不仅促进星形胶质细胞发生，还阻止少突胶质细胞分化，我们假设 BMP4 的旁分泌作用，局限于神经血管单元内，促进白质紊乱和神经退行性变。这些观察结果表明，衰老大脑血管中的 BMP4 信号通路是一个潜在的治疗靶点。最后，由于部分 eNOS 缺陷小鼠的研究证实了最近的临床证据，即血脑屏障破坏是白质病变的主要原因，因此，一氧化氮信号介导的 CSVD 受损机制值得进一步研究。
