Kamal Narayana, Imelda Lambert, S. R. Burford, Emily Gosselin, Jakob Körbelin, Craig E. Brown
Focal stroke leads to complex changes in the cerebral microcirculation in surviving brain tissues that strongly influence functional recovery. The gene Serpine1 and its protein product Plasminogen Activator-Inhibitor-1 (PAI-1), are highly upregulated in endothelial cells after stroke, are known to inhibit clot breakdown and are an established biomarker of cardiovascular disease in humans. Therefore, we hypothesized that inhibiting this pathway specifically within brain endothelial cells could be beneficial for stroke recovery by promoting fibrinolysis and cerebral blood flow (CBF). Using longitudinal in vivo imaging, we first show in wild-type mice that focal ischaemic stroke leads to a transient reduction in peri-infarct CBF at 6 h (~41%), which is then followed by hyperperfusion at 3 days (~29%). Contrary to expectation, viral knockdown of Serpine1 in brain endothelial cells led to a persistent reduction in peri-infarct capillary width (~20-37%) and red blood cell velocity (~36-50%) over this time. Consistent with this effect on CBF, topical application of PAI-1 increased capillary diameter and flow. Of note, lowered peri-infarct CBF in Serpine1 knockdown mice appeared to play a protective role in stroke recovery since it attenuated deleterious blood-brain barrier disruption and pro-inflammatory gene expression. In agreement with this, Serpine1 knockdown mice displayed enhanced recovery of sensory evoked cortical responses, as well as improved cognitive and sensorimotor function relative to wild-type mice. These findings suggest that endothelial Serpine1/PAI-1 signalling can influence vessel tone and highlight its therapeutic potential in promoting stroke recovery. Further, our data challenge the assumption that increased CBF after the hyper-acute phase of stroke is better for recovery and suggest that carefully tuning flow, rather than maximizing it, may be an optimal strategy.