TY - JOUR

T1 - Dynamic capillary stalls in reperfused ischemic penumbra contribute to injury

T2 - A hyperacute role for neutrophils in persistent traffic jams

AU - Erdener, Sefik E.

AU - Tang, Jianbo

AU - Kilic, Kivilcim

AU - Postnov, Dmitry

AU - Giblin, John T.

AU - Kura, Sreekanth

AU - Chen, I-Chun A.

AU - Vayisoglu, Tugberk

AU - Sakadzic, Sava

AU - Schaffer, Chris B.

AU - Boas, David A.

PY - 2021

Y1 - 2021

N2 - Ever since the introduction of thrombolysis and the subsequent expansion of endovascular treatments for acute ischemic stroke, it remains to be identified why the actual outcomes are less favorable despite recanalization. Here, by high spatio-temporal resolution imaging of capillary circulation in mice, we introduce the pathological phenomenon of dynamic flow stalls in cerebral capillaries, occurring persistently in salvageable penumbra after reperfusion. These stalls, which are different from permanent cellular plugs of no-reflow, were temporarily and repetitively occurring in the capillary network, impairing the overall circulation like small focal traffic jams. In vivo microscopy in the ischemic penumbra revealed leukocytes traveling slowly through capillary lumen or getting stuck, while red blood cell flow was being disturbed in the neighboring segments under reperfused conditions. Stall dynamics could be modulated, by injection of an anti-Ly6G antibody specifically targeting neutrophils. Decreased number and duration of stalls were associated with improvement in penumbral blood flow within 2-24 h after reperfusion along with increased capillary oxygenation, decreased cellular damage and improved functional outcome. Thereby, dynamic microcirculatory stall phenomenon can be a contributing factor to ongoing penumbral injury and is a potential hyperacute mechanism adding on previous observations of detrimental effects of activated neutrophils in ischemic stroke.

AB - Ever since the introduction of thrombolysis and the subsequent expansion of endovascular treatments for acute ischemic stroke, it remains to be identified why the actual outcomes are less favorable despite recanalization. Here, by high spatio-temporal resolution imaging of capillary circulation in mice, we introduce the pathological phenomenon of dynamic flow stalls in cerebral capillaries, occurring persistently in salvageable penumbra after reperfusion. These stalls, which are different from permanent cellular plugs of no-reflow, were temporarily and repetitively occurring in the capillary network, impairing the overall circulation like small focal traffic jams. In vivo microscopy in the ischemic penumbra revealed leukocytes traveling slowly through capillary lumen or getting stuck, while red blood cell flow was being disturbed in the neighboring segments under reperfused conditions. Stall dynamics could be modulated, by injection of an anti-Ly6G antibody specifically targeting neutrophils. Decreased number and duration of stalls were associated with improvement in penumbral blood flow within 2-24 h after reperfusion along with increased capillary oxygenation, decreased cellular damage and improved functional outcome. Thereby, dynamic microcirculatory stall phenomenon can be a contributing factor to ongoing penumbral injury and is a potential hyperacute mechanism adding on previous observations of detrimental effects of activated neutrophils in ischemic stroke.

KW - Cerebral ischemia

KW - capillary

KW - microcirculation

KW - neutrophil

KW - stall

KW - CEREBRAL-ARTERY OCCLUSION

KW - SELECTIVE NEURONAL LOSS

KW - PROVIDES NEUROPROTECTION

KW - STROKE

KW - BRAIN

KW - MOUSE

KW - PERFUSION

KW - ADHESION

KW - MODELS

KW - DEPOLARIZATIONS

U2 - 10.1177/0271678X20914179

DO - 10.1177/0271678X20914179

M3 - Journal article

C2 - 32237951

VL - 41

SP - 236

EP - 252

JO - Journal of Cerebral Blood Flow and Metabolism

JF - Journal of Cerebral Blood Flow and Metabolism

SN - 0271-678X

IS - 2

ER -