Peri-Microvascular Glycogen and Lactate Regulate Capillary Constrictions and Ischemia Outcome in Mice

Ischemic stroke results in sudden blood flow cessation, thus unmet energy requirements. Glycogen stored around peri-microvascular astrocyte end-feet may mediate capillary contractility and cerebral blood flow alterations. Under glucose-deprived and hypoxic conditions, lactate derived from these glycogen stores may serve as an emergency fuel to sustain tissue perfusion during an acute period of ischemic stroke. To elucidate the impact of glycogen utilization on brain microcirculation, both 1,4-dideoxy-1,4-imino-d-arabinitol hydrochloride (DAB) administered to wild-type (WT) intracerebroventricularly (i.c.v.), and central nervous system and astrocyte-specific glycogen synthase-1 knock-out (GYS1^Nestin-KO and GYS1^Gfap-KO) mice were used. We assessed regional cerebral blood flow changes in vivo, pericyte-associated microvascular constrictions, semi-quantitative peri-microvascular glycogen levels, and lactate transporters ex vivo. Experiments revealed that both pharmacological and genetic manipulations of glycogen metabolism also resulted in severely compromised blood flow dynamics and higher infarct volumes after stroke. Disrupted cerebral glycogen utilization induced CD13-positive pericyte-associated microvascular constrictions, which were highly correlated with peri-microvascular periodic acid Schiff (PAS), IV58B6, and ESG1A9 intensity levels. Lastly, intravenous (i.v.) D/L-lactate and i.c.v. L-lactate administration reversed microvascular constrictions while glycogen phosphorylase inhibition potently reduced microvascular monocarboxylate transporter-1 (MCT1) coverage. In conclusion, disrupted glycogen utilization causes ischemic-like microvascular constrictions, increases susceptibility to brain ischemia, and is reversible with systemic lactate administration. Understanding the role of glycogen and lactate metabolism at the neurogliovascular level in the brain may provide novel insight into the pathophysiology and therapeutic opportunities of cerebrovascular disorders.