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

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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.