Knockdown of endothelial Serpine1 improves stroke recovery by attenuating peri-infarct blood flow and blood brain barrier disruption

Abstract

Focal stroke leads to complex changes in the cerebral microcirculation in surviving brain tissues that strongly influence recovery. Plasminogen activator inhibitor-1 (PAI-1; encoded by Serpine1) is highly upregulated in endothelial cells after stroke. Since the primary function of PAI-1 is to inhibit fibrin clot breakdown, we hypothesized that blocking this pathway would be beneficial for recovery since it is expected to increase capillary blood flow after stroke. Using longitudinal in vivo imaging in mice subjected to ischemic stroke, we unexpectedly found that knockdown of Serpine1 in brain endothelial cells leads to a long-lasting reduction in peri-infarct capillary width, red blood cell velocity and flux. Conversely, stimulating this pathway in naive mice increased capillary width and blood flow. Lowered peri-infarct blood flow in Serpine1 knockdown mice attenuated deleterious blood brain barrier disruption and pro-inflammatory gene expression. Serpine1 knockdown improved the progressive recovery of sensory evoked cortical responses, as well as cognitive and sensorimotor function. These findings challenge the assumption that increased blood flow after stroke is better for recovery and reveal that carefully tuning flow, rather than maximizing it, may be optimal. Further our data highlight the therapeutic potential of targeting endothelial Serpine1/PAI-1 signalling in promoting stroke recovery.