Translational analysis of cerebrovascular dysfunction in aging

摘要 与年龄相关的血管认知障碍(VCI)和步态异常是导致 老年人的残疾会导致丧失独立性并严重降低生活质量。最新研究 结论：脑微血管病变在VCI和VCI的表现中起重要作用 步态异常。脑血管的基本作用之一是匹配脑血流量(Cbf)。 通过一种称为神经血管耦合(NVC)的过程对神经元进行能量需求。NVC维护 最佳脑组织微环境，需要一氧化氮(NO)诱导的微血管扩张 脑微血管内皮细胞(CMVECs)在神经元/星形胶质细胞激活时释放。 最近的研究表明，抑制NO介导的NVC反应会导致小鼠认知功能受损 表现和步态异常。重要的是，调节动物NVC和认知的因素之一 Models是一种血管保护激素胰岛素样生长因子-1(IGF-1)，已被证明随着 年龄并影响大脑中的许多细胞类型。最近的研究结果表明，与年龄相关的循环IGF-1水平下降 1促进应激和DNA损伤，并与细胞标志物表达增加有关 脑和主动脉的衰老。尽管最近取得了进展，但我们对以下问题的理解存在严重差距 在衰老过程中促进脑微血管内皮细胞功能障碍的特定分子机制 循环IGF-1的年龄依赖性缺陷是否与NVC及更高级别的损害有关 人类的大脑功能(包括认知和步态)。我们的总体假设是年龄相关的IGF-1 缺乏通过诱导内皮细胞衰老来促进NVC中的内皮功能障碍和损伤， 这会导致老年动物和人类的认知障碍和步态异常。以下目标 建议：目的1)评估NVC功能障碍是否通过IGF-1的特定作用而介导 CMVECs的缺陷以及内皮细胞衰老是否参与了这种损伤。为了实现这一目标，我们 将使用专门针对内皮细胞的干扰IGF-1信号的新模型和新的小鼠模型 (p16-3MR)，它允许专门消除衰老细胞。目标2)确定 受试者的年龄、循环IGF-1状态、内皮功能、NVC反应、认知和步态。

ABSTRACT Age-related vascular cognitive impairment (VCI) and gait abnormalities are the two most common causes of disability in older adults that lead to loss of independence and severely reduce quality of life. Recent studies have concluded that cerebromicrovascular pathologies play an important role in the manifestation of VCI and gait abnormalities. One of the fundamental roles of the cerebrovasculature is to match cerebral blood flow (CBF) with energetic demands of neurons through a process known as neurovascular coupling (NVC). NVC maintains an optimal cerebral tissue microenvironment and requires microvascular dilation induced by nitric oxide (NO) released from cerebromicrovascular endothelial cells (CMVECs) in response to neuronal/astrocytic activation. Recent studies demonstrate that inhibition of NO-mediated NVC responses in mice results in impaired cognitive performance and gait abnormalities. Importantly, one of the factors that regulates NVC and cognition in animal models is the vasoprotective hormone insulin-like growth factor-1 (IGF-1) that has been shown to decrease with age and influences many cell-types in brain. Recent findings suggest that age-related decline of circulating IGF- 1 promotes stress and DNA damage and is associated with increased expression of markers of cellular senescence in brain and aorta. Despite recent advances, there is a critical gap in our understanding related to specific molecular mechanisms that promote cerebromicrovascular endothelial dysfunction in aging, and whether the age-dependent deficiency of circulating IGF-1 is associated with impairments in NVC and higher brain functions (including cognition and gait) in humans. Our overall hypothesis is that age-associated IGF-1 deficiency promotes endothelial dysfunction and impairments in NVC by inducing endothelial cell senescence, which contribute to cognitive impairment and gait abnormalities in older animals and humans. The following aims are proposed: Aim 1) Assess whether dysfunction of NVC is mediated through a specific effect of IGF-1 deficiency on CMVECs and whether endothelial cell senescence contributes to this impairment. In this aim we will use novel model ofdisruption of IGF-1 signaling specifically in endothelial cells and a novel mouse model (p16-3MR) which allows to specifically eliminate senescent cells. Aim 2) Determine the relationship between age, circulating IGF-1 status, endothelial function, NVC responses, cognition and gait in human subjects.