Angiophagy: mechanism of microvascular recanalization independent of the fibrinolytic system.

C ell viability in the brain is critically dependent on uninterrupted blood flow through the microvasculature. However, microvessels, because of their small diameter and low-flow velocity, are prone to occlusion by blood clots, fragments of atheromatous plaques, or other circulating debris. Furthermore, microvascular occlusions can occur after large-vessel thrombosis because of blood stasis or due to clot fragmentation and distal microembolization. Microvascular occlusion could thus be a frequent phenomenon throughout life that may play important roles in the pathogenesis of cere-bral ischemia and reperfusion, age-related vascular cognitive impairment, and cognitive decline after surgical procedures, such as coronary artery bypass graft. Given the propensity of microvessels to occlusion, it is likely that robust mechanisms have evolved to ensure micro-vascular patency. The main mechanism that prevents micro-vascular occlusion is constituted by the combined effects of the fibrinolytic system and hemodynamic pressure, which lead to embolus dissolution and washout. However, the fibrinolytic system is limited to breaking down fibrin-based blood clots and is unable to disrupt other materials, such as calcium and cholesterol crystals and cell debris, which are present in complex thrombi and may occlude microvessels throughout life. Using an experimental mouse model of internal carotid embolization with fluorescently labeled microemboli (10–60 µm), we were able to study the outcome of individual micro-vascular occlusions in the mouse brain. We tracked individual microvessels using high-resolution confocal imaging in histo-logical brain preparations and by time-lapse 2 photon micros-copy of the meninges and superficial cortex in living mice. Using these methods, we recently found a novel mechanism of microvascular recanalization, which we termed " angiophagy. " This mechanism involves the engulfment of emboli by the endothelium followed by their translocation through the vessel wall into the perivascular space. Angiophagy is a robust mechanism that leads to blood flow reestablishment within hours of the embolus extrusion. 1 Embolus extravasation occurs 1 to 6 days after occlusion in >80% of occluded vessels ranging from terminal capillaries (≈7 µm) to arterioles (≈60 µm) in various organs, including the brain, retina, heart, muscle, lung, and kidney. The speed of translocation seems to be heterogeneous and may depend on variables such as vessel location, size of embolus, and type of embolic material (fibrin clots extravasate somewhat faster than cholesterol crystals). The vast majority of vessels that undergo successful emboli extrusion do not display any evidence of endothelial or mural cell death, as evidenced by normal nuclear and cellular morphology and …