Per-ischemic changes in penumbral blood supply and its microscopic distribution

Acute ischemic stroke (AIS) is a frequent cause of death and adult disability. AIS patient management targets the ischemic penumbra: Hypoperfused, electrically silent brain tissue, which can be salvaged by restoring blood flow during the first, critical hours after symptom onset. Neuroimaging studies in AIS patients suggest that penumbral tissue is characterized not only by hypoperfusion, but also by microvascular flow disturbances that strongly affect tissue outcome. Here, we demonstrate that microvascular flows become increasingly chaotic in the ischemic penumbra in the hours after middle cerebral artery occlusion in a rat model of AIS. Biophysical models suggest that these disturbances are accompanied by increasing hypoxia in the absence of blood flow changes. Unlike findings in severe ischemia, pericyte constrictions do not appear to occlude penumbral capillaries. We propose that microvascular flow disturbances represent a critical feature of penumbral tissue, and a potential target for neuroprotective therapy after AIS.