Quantifying the Influence of Pathological Hemodynamics on Cerebral Microvascular Dysfunction and Neuronal Injury

项目摘要 痴呆症是一种使人衰弱的综合征，有许多失能症状，需要依赖性护理， 对患者及其家庭造成情感和经济负担。痴呆症是第六大原因 目前全球有4750万人患有痴呆症，预计 到2030年达到7560万，到2050年达到1.355亿。不幸的是，没有治疗痴呆症的疗法存在， 这表明迫切需要更好地了解痴呆症是如何开始和发展的， 可以开发新的治疗方法。大弹性动脉的硬化是一个主要的 这是痴呆症的一个促成因素，但其发生的机制仍不清楚。在健康的个体中， 大血管中的脉动流通过脉动阻尼转换为脑微血管中的连续流 大动脉。随着时间的推移，重复的扩张和松弛循环会导致不可逆的弹性蛋白断裂 在大动脉中，其被更硬的胶原蛋白取代，从而降低顺应性和阻尼。这导致 在脑微血管中从连续流到脉动流的转换中，伴随着 脉压和脉搏波速度。这些病理性血流动力学与认知能力下降有关 通过神经元损伤、突触功能障碍和神经变性。虽然大多数假设都集中在剪切- 诱导损伤机制，内皮细胞和神经元也对应变敏感。我们假设 - 由于转换成脉动流，在微血管壁和邻近组织中诱导循环应变， 加剧了剪切诱导的脑微血管内皮细胞（BMEC）功能障碍，是 神经元损伤我们将通过实现两个目标来检验我们的假设。(1)独立调查， 循环剪应力和循环应变对BMEC的综合影响、向循环剪应力和循环应变的转换以及循环剪应力和循环应变的增加对BMEC的综合影响 功能障碍和炎症。我们假设，从连续流到脉动流的转换， 在脉搏波速度中，通过暴露于增加循环剪切应力而诱导BMEC功能障碍和炎症。 我们进一步假设，微血管壁中的周期性应变，以及应变幅度的增加， 脉压增加，加剧剪切诱导的BMEC功能障碍。(2)调查循环的影响 神经元损伤的应变。我们假设，随着脉压的增加，相关的应变增加， 通过应变传播到邻近血管的组织和神经元中诱导神经元损伤， 与年龄有关的大脑软化的痴呆症。该提案的结果将提供重要的见解， 动脉硬化引起的病理性血流动力学改变导致BMEC和神经元损伤。

PROJECT SUMMARY Dementia is a debilitating syndrome with many incapacitating symptoms requiring dependent care that is emotionally and financially burdensome for patients and their families. Dementia is the 6th leading cause of death in the United States with 47.5 million people worldwide currently living with dementia which is projected to reach 75.6 million by 2030 and 135.5 million by 2050. Unfortunately, no therapies to treat dementia exist, indicating a critical and urgent need for a better understanding of how dementia is initiated and progresses so that new therapeutic approaches can be developed. Age-related stiffening of the large elastic arteries is a major contributor to dementia but the mechanism(s) by which this occurs remain unknown. In healthy individuals, pulsatile flow in large vessels is converted to continuous flow in cerebral µvasculature via pulsatility dampening by large arteries. Repeated cycles of distension and relaxation over time induce irreversible elastin fragmentation in large arteries which is replaced by stiffer collagen thereby diminishing compliance and dampening. This results in the conversion from continuous to pulsatile flow in cerebral microvasculature accompanied by increases in pulse pressure and pulse wave velocity. These pathological hemodynamics have been linked to cognitive decline via neuronal injury, synaptic dysfunction, and neurodegeneration. While most hypotheses focus on shear- induced injury mechanisms, endothelial cells and neurons are also sensitive to strain. We hypothesize that induction of cyclic strain, in the microvessel wall and adjacent tissue, due to the conversion to pulsatile flow, exacerbates shear-induced brain microvascular endothelial cell (BMEC) dysfunction and is the primary cause of neuronal injury. We will test our hypotheses via fulfillment of two aims. (1) Investigate the independent, and combined influences of, conversion to, and increases in, cyclic shear stress and cyclic strain on BMEC dysfunction and inflammation. We hypothesize that conversion from continuous to pulsatile flow, and an increase in pulse wave velocity, induce BMEC dysfunction and inflammation via exposure to increased cyclic shear stress. We further hypothesize that cyclic strain in the microvascular wall, and increase in strain magnitude due to increased pulse pressure, exacerbate shear-induced BMEC dysfunction. (2) Investigate the influence of cyclic strain on neuronal injury. We hypothesize that as pulse pressure increases, the associated increase in strain will induce neuronal injury via strain propagation into tissue and neurons adjacent to the vessel and that this process worsens with age-related brain softening. The results of this proposal will provide significant insight into how pathological hemodynamics induced by arterial stiffening lead to BMEC and neuronal injury.