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.

Occlusion of the microvasculature by blood clots, atheromatous fragments, or circulating debris is a frequent phenomenon in most human organs. Emboli are cleared from the microvasculature by hemodynamic pressure and the fibrinolytic system. An alternative mechanism of clearance is angiophagy, in which emboli are engulfed by the endothelium and translocate through the microvascular wall. We report that endothelial lamellipodia surround emboli within hours of occlusion, markedly reducing hemodynamic washout and tissue plasminogen activator-mediated fibrinolysis in mice. Over the next few days, emboli are completely engulfed by the endothelium and extravasated into the perivascular space, leading to vessel recanalization and blood flow reestablishment. We find that this mechanism is not limited to the brain, as previously thought, but also occurs in the heart, retina, kidney, and lung. In the lung, emboli cross into the alveolar space where they are degraded by macrophages, whereas in the kidney, they enter the renal tubules, constituting potential routes for permanent removal of circulating debris. Retina photography and angiography in patients with embolic occlusions provide indirect evidence suggesting that angiophagy may also occur in humans. Thus, angiophagy appears to be a ubiquitous mechanism that could be a therapeutic target with broad implications in vascular occlusive disorders. Given its biphasic nature-initially causing embolus retention, and subsequently driving embolus extravasation-it is likely that different therapeutic strategies will be required during these distinct post-occlusion time windows.