Embolus extravasation is an alternative mechanism for cerebral microvascular recanalization

Cerebral microvascular occlusion is a common phenomenon throughout life1,2 that could be an underappreciated mechanism of brain pathology. Failure to promptly recanalize microvessels may lead to disruption of brain circuits and significant functional deficits3. Hemodynamic forces and the fibrinolytic system4 are considered the principal mechanisms responsible for recanalization of occluded cerebral capillaries and terminal arterioles. However, using high resolution fixed tissue microscopy and two photon imaging in living mice we found that a large fraction of occluding microemboli failed to be lysed and washed out within 48 hours after internal carotid infusion. Surprisingly, emboli were instead found to translocate outside the vessel lumen within 2-7 days leading to complete re-establishment of blood flow and sparing of the vessel. Recanalization occurred by a previously unknown mechanism of microvascular plasticity involving the rapid envelopment of emboli by endothelial membrane projections which subsequently form a new vessel wall. This was followed by the formation of an endothelial opening through which emboli translocated into the perivascular parenchyma. The rate of embolus extravasation was significantly reduced by pharmacological inhibition of matrix metalloproteinase 2/9 activity. In aged mice, extravasation was markedly delayed, resulting in persistent tissue hypoxia, synaptic damage and cell death. Our study identifies a novel cellular mechanism that may be critical for recanalization of occluded microvessels. Alterations in the efficiency of this protective mechanism may have important implications in microvascular pathology, stroke recovery, and age-related cognitive decline.