The impact of microvascular (dys)regulation on cerebral flow and oxygen heterogeneity

摘要 由于大脑皮层没有能量储备，它需要紧耦合的供应之间的 营养和氧气以及组织的新陈代谢需求。小血管，从这些血管 营养物质和氧气被认为是高度异质的结构 和功能。这种异质性在生理条件下的性质和作用以及它是如何 可能导致的病理还没有完全了解。微循环的大小和复杂程度 缺乏能够测量微循环动态的技术阻碍了 进步。需要具有高时空分辨率的复杂成像工具来 研究了毛细网络的动态非均质性。这对于以下方面尤其重要 研究我们最近在微血管内的一种新的动态现象 观察到并牵涉到脑部疾病。具体地说，血液流动的暂时中断 单个大脑毛细血管(即RBC停滞)的发生是由于细胞与 血管内皮细胞穿过狭窄的毛细血管管腔，以及这些间歇的频率 随着血细胞计数增加，炎症加剧，淀粉样蛋白表达增强- β(模拟阿尔茨海默病(AD))和脑缺血。这些摊位被观察到 由于尚未确定的原因，反复出现在某些毛细血管中。毛细管可能停滞 在非常局部的水平上引入流动的不均一性和降低的氧气压力，但是 此外，累积起来，它们可能会对全球产生影响，无论是否会降低大脑 血液流动。重要的是，我们的团队已经证明，从药物上降低 AD模型中的这些停滞立即导致认知能力的改善。这 清楚地表明了理解普遍机制和更广泛的 这些拖延事件的含义可能导致各种认知能力的下降 条件。我们的团队一直在开发一套工具，这些工具特别适合研究 微血管网络的结构和功能异质性及其对组织的影响 氧气的输送和功能。我们建议扩展和优化我们的技术，以 阐明正常生理学中毛细血管停滞的具体原因，为什么它们会反复发生 在某些节段，如果它们在神经血管耦合的毛细血管水平调节中起到任何作用， 以及它们对大脑新陈代谢和细胞功能的影响。

ABSTRACT As the cerebral cortex has no energy reserve, it requires a tight coupling between the supply of nutrients and oxygen and the metabolic demand of the tissue. Small blood vessels, from which nutrients and oxygen are supplied, are hypothesized to be highly heterogeneous in structure and function. The nature and role of this heterogeneity under physiological conditions and how it may lead to pathologies is not fully understood. The size and complexity of the microcirculation and lack of technologies capable of measuring dynamics of the microcirculation have hindered progress. Sophisticated imaging tools with high spatiotemporal resolution are necessary to study the dynamic heterogeneity of the capillary network. This is particularly important for studying a new dynamic phenomenon within the microvasculature which we have recently observed and implicated in brain disease. Specifically, temporary interruptions of blood flow in individual cerebral capillaries (i.e. RBC stalls) are occurring due to the adhesion of cells to the endothelium while passing through the narrow capillary lumen, and the frequency of these stalls increases with high blood cell counts, enhanced inflammation, enhanced expression of amyloid- beta (modeling Alzheimer’s disease (AD)) and cerebral ischemia. These stalls are observed to occur repeatedly in certain capillaries for yet undetermined reasons. Capillary stalls likely introduce flow heterogeneity and pockets of decreased oxygen tension at a very local level, but also, cumulatively, they can have global consequences with or without decreasing the cerebral blood flow. Importantly, our team has shown that pharmacologically reducing the incidence of these stalls in an AD model immediately resulted in improved cognitive performance. This clearly indicates the importance of understanding the universal mechanisms and broader implications of these stalling events that likely result in cognitive decline in a variety of conditions. Our team has been developing a suite of tools that are uniquely suited to study the structural and functional heterogeneity of the microvascular network and the impact on tissue oxygen delivery and function. We are proposing to extend and optimize our techniques to elucidate the specific causes of capillary stalls in normal physiology, why they repeatedly occur in certain segments, if they have any role in capillary-level regulation of neurovascular coupling, and what consequences they have on cerebral metabolism and cell function.