Perivascular macrophages mediate the neurovascular and cognitive dysfunction associated with hypertension
Perivascular macrophages mediate the neurovascular and cognitive dysfunction associated with hypertension
复制标题
DOI：
10.1172/jci86950
复制
发表时间：
2016-12-01
影响因子：
15.9
通讯作者：
Iadecola, Costantino
中科院分区：
文献类型：
--
作者：
Faraco, Giuseppe;Sugiyama, Yukio;Iadecola, Costantino
高血压是痴呆症的主要危险因素，但其对大脑破坏性影响的潜在机制尚不清楚。由于缺乏能量储备，大脑依赖于根据其动态代谢需要不断向其活跃区域输送血液。高血压会破坏这些重要的调节机制，导致神经元功能障碍和潜在的认知障碍。阐明这些损伤的细胞基础对于开发新的治疗方法至关重要。血管周围巨噬细胞（pvm）是一种独特的常驻脑巨噬细胞，具有关键的体内平衡作用，但也具有产生大量活性氧（ROS）的潜力。在这里，我们报道pvm在高血压小鼠模型中驱动神经血管调节的改变和随之而来的认知障碍方面是至关重要的。这种作用是通过血脑屏障通透性的增加介导的，这使得血管紧张素II进入血管周围空间，激活pvm中的血管紧张素1型受体，导致通过超氧化物生成酶NOX2产生ROS。这些发现揭示了pvm在高血压相关的神经血管和认知功能障碍中的致病作用，并将这些细胞确定为脑血管氧化应激相关疾病的假定治疗靶点。
Hypertension is a leading risk factor for dementia, but the mechanisms underlying its damaging effects on the brain are poorly understood. Due to a lack of energy reserves, the brain relies on continuous delivery of blood flow to its active regions in accordance with their dynamic metabolic needs. Hypertension disrupts these vital regulatory mechanisms, leading to the neuronal dysfunction and damage underlying cognitive impairment. Elucidating the cellular bases of these impairments is essential for developing new therapies. Perivascular macrophages (PVMs) represent a distinct population of resident brain macrophages that serves key homeostatic roles but also has the potential to generate large amounts of reactive oxygen species (ROS). Here, we report that PVMs are critical in driving the alterations in neurovascular regulation and attendant cognitive impairment in mouse models of hypertension. This effect was mediated by an increase in blood-brain barrier permeability that allowed angiotensin II to enter the perivascular space and activate angiotensin type 1 receptors in PVMs, leading to production of ROS through the superoxide-producing enzyme NOX2. These findings unveil a pathogenic role of PVMs in the neurovascular and cognitive dysfunction associated with hypertension and identify these cells as a putative therapeutic target for diseases associated with cerebrovascular oxidative stress.