Translational analysis of cerebrovascular dysfunction in aging

摘要 脑血管病相关的血管性认知障碍（VCI）和步态异常是两种最常见的原因， 老年人的残疾导致失去独立性，严重降低生活质量。最近的研究 得出结论，微血管病变在VCI的表现中起重要作用， 步态异常脑血管系统的基本作用之一是匹配脑血流量（CBF） 通过一个被称为神经血管耦合（NVC）的过程来满足神经元的能量需求。雷士认为， 最佳脑组织微环境，需要一氧化氮（NO）诱导的微血管扩张 从微血管内皮细胞（CMVEC）中释放，以响应神经元/星形胶质细胞活化。 最近的研究表明，在小鼠中抑制NO介导的NVC反应会导致认知功能受损， 表现和步态异常。重要的是，调节动物NVC和认知的因素之一 模型是血管保护激素胰岛素样生长因子-1（IGF-1），已被证明随着 年龄和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促进应激和DNA损伤，并与细胞凋亡标志物的表达增加有关。 脑和主动脉衰老。尽管最近取得了一些进展，但我们对以下问题的理解仍存在重大差距： 促进衰老中微血管内皮功能障碍的特定分子机制， 年龄依赖性循环IGF-1缺乏是否与NVC和更高水平的损伤相关 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 目的：1）评估NVC功能障碍是否通过IGF-1的特异性作用介导 缺乏CMVEC和内皮细胞衰老是否有助于这种损害。为此，我们 将使用一种新的内皮细胞IGF-1信号转导破坏模型和一种新的小鼠模型 （p16 - 3MR），其允许特异性消除衰老细胞。（2）确定关系 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.