Embolus extravasation is an alternative mechanism for cerebral microvascular recanalization

Abstract

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.

Reduction in Distal Emboli With Proximal Flow Control During Mechanical Thrombectomy

“…However, based on the previous research, we have learned the following: (1) a presumable inverse relationship exists between the size and number of the disrupted clots required to create cerebral ischemia and infarction, 22 (2) most distal protection devices for carotid stenting have a pore size between 100 and 200 µm, suggesting particles with size <100 to 200 µm are less likely to result in severe embolic stroke, 23,24 and (3) other than the fibrinolytic system and hemodynamic forces, recanalization of cerebral microvascular occlusion could be achieved by embolus extravasation. 25,26 As documented in a recent clinical report, 27 among all the clot debris, a small fraction were larger fragments with size between 200 and 1600 μm. The number of these particles was significantly less than that of the small debris; however, they are thought to lead to significant cerebral occlusions.…”

Can Restoring Incomplete Microcirculatory Reperfusion Improve Stroke Outcome after Thrombolysis?

“…An elegant study has recently shown that part of the microemboli (8 to 20 mm) are cleared from microcirculation within 2 hours after their infusion into the carotid artery in mice. 85 Yet, a substantial number of emboli are retained in the microvasculature and interrupt the blood flow. Obstructed microvessel lumina reopen after extravasation of the clot to the perivascular area within the following days.…”

In Vivo Imaging of Neurovascular Remodeling After Stroke

“…16 Envelopment of emboli by endothelial membrane projections followed by expulsion into perivascular parenchyma was detected after a few days. This process may be a critical endogenous mechanism through which reestablishment of perfusion occurs after occlusion of cerebral microvessels.…”