Disrupted Cerebral Peri-Microvascular Glycogen Promotes Capillary Constrictions And Aggravates Ischemia In Mice

Ischemic stroke results in sudden blood flow cessation, thus, unmet energy requirements. Although the clotted artery can be recanalized and blood flow is restored, brain perfusion may not be fully attained due to microvascular constrictions. Under glucose deprived and hypoxic conditions, glucose derived from the glycogen stored around peri-microvascular astrocyte end-feet may serve as an emergency fuel to meet the metabolic demand during acute period of ischemic stroke. To elucidate the impact of glycogen utilization on brain microcirculation, we administered glycogen phosphorylase inhibitor 1,4-dideoxy-1,4-imino-d-arabinitol (DAB) intracerebroventricularly. Transgenic mice in which glycogen synthase-1 expression was selectively knocked out in central nervous system (GYS1Nestin-KO) were also used. Both approaches caused microvascular constrictions mediated by CD13-positive pericyte contractions. When mice with disrupted glycogen utilization were subjected to MCA ischemia, pericyte-mediated microvascular constrictions and the infarct volumes were further increased compared to untreated controls or wild type littermates. Perimicrovascular glycogen depletions were highly correlated with microvascular constrictions as shown by Periodic acid Schiff (PAS) staining and immunolabeling with anti-glycogen antibodies. Imaging of regional cortical blood flow changes during ischemia disclosed severely compromised blood flow dynamics in mice with disrupted glycogen metabolism. In conclusion, disrupting glycogen utilization causes ischemic-like microvascular constrictions under non-ischemic circumstances and increases susceptibility to brain ischemia. Understanding the role of glycogen at neurogliovascular level in brain may provide novel insight to the pathophysiology of ischemic stroke and therapeutic opportunities. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=142 SRC="FIGDIR/small/505172v1_ufig1.gif" ALT="Figure 1"> View larger version (33K): org.highwire.dtl.DTLVardef@1a4972borg.highwire.dtl.DTLVardef@c09847org.highwire.dtl.DTLVardef@4d961forg.highwire.dtl.DTLVardef@1bae0de_HPS_FORMAT_FIGEXP M_FIG C_FIG