Embolus extravasation is an alternative mechanism for cerebral microvascular recanalization

Abstract

Throughout our lives, tiny blood clots or microemboli develop in the blood vessels of the brain. Many are removed by the force of the blood flow and others are digested by fibrinolysis. Now a third embolus removal mechanism has been discovered: embolus extravasation. High-resolution fixed tissue microscopy and two-photon imaging in live mice shows that many microemboli are not lysed by blood or fibrinolysis, but are instead actively removed within a week by endothelial cells that envelop the emboli, as the underlying endothelium is remodelled to produce an unblocked blood vessel. This process takes longer in aged mice, suggesting that clot-clearance is a possible therapeutic target in patients recovering from a stroke or for age-related cognitive disorders. Uninterrupted blood flow through the small vessels of the brain is essential for cerebral function and viability. Small clots that form in the vessels can be — but are not always — removed by haemodynamic forces and the fibrinolytic system. Here, a third mechanism for the removal of emboli is described: the endothelial cells that line the vessel walls send out membrane projections that envelop the emboli and move them into the perivascular parenchyma tissue. In aged mice, this process is markedly delayed. Cerebral microvascular occlusion is a common phenomenon throughout life1,2 that might require greater recognition as a mechanism of brain pathology. Failure to recanalize microvessels promptly may lead to the disruption of brain circuits and significant functional deficits3. Haemodynamic forces and the fibrinolytic system4 are considered to be the principal mechanisms responsible for recanalization of occluded cerebral capillaries and terminal arterioles. Here we identify a previously unrecognized cellular mechanism that may also be critical for this recanalization. By using high-resolution fixed-tissue microscopy and two-photon imaging in living mice we observed that a large fraction of microemboli infused through the internal carotid artery failed to be lysed or washed out within 48 h. Instead, emboli were 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 that 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 decreased 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. Alterations in the efficiency of the protective mechanism that we have identified may have important implications in microvascular pathology, stroke recovery and age-related cognitive decline.