Robert Flaumenhaft, MD, PhD
Dr. Flaumenhaft indicated no relevant conflicts of interest.
Lam CK, Yoo T, Hiner B, et al. Embolus extravasation is an alternative mechanism for cerebral microvascular recanalization. Nature. 2010;465:478-482.
Maintenance of blood flow through the cerebral microvasculature is essential to normal cerebral function. Fibrinolysis and hemodynamic forces clear fibrin-rich clots from the cerebral microcirculation rapidly and efficiently. However, fragments from atherosclerotic plaque and complex clots not susceptible to fibrinolysis can also occlude the cerebral microvasculature. Such emboli are not effectively cleared by the fibrinolytic system. What is the fate of these fragments? Lam et al. from Northwestern University in Chicago have now identified a heretofore unrecognized mechanism for maintaining patency of the microvasculature. They demonstrated that the endothelium is capable of clearing the microvasculature of occlusive emboli by translocation, thereby restoring blood flow.
The investigators used transcranial two-photon microscopy of the cerebral microvasculature to evaluate the fate of fluorescent fibrin clots, cholesterol emboli, and microspheres infused through the internal carotid arteries of mice. Mice expressing Tie2-green fluorescent protein were used in these studies to visualize the endothelium following infusion of fluorescent emboli. The investigators found that emboli that were not lysed within the first few hours following infusion were extravasated from the vessel over a two- to seven-day period. Electron microscopy of tissue samples from these mice confirmed that the emboli had been extruded into the surrounding tissue. An open luminal space completely surrounded by an endothelial layer was observed next to the extravasated emboli, consistent with the observation that blood flow is restored after translocation. Time-lapse imaging demonstrated how the endothelium generated the proto-lumen. Endothelial membrane projections formed around the emboli. The new endothelium grew all the way around the emboli to create the proto-lumen (Figure). The original endothelium concurrently underwent retraction, enabling the extravasation of emboli into the perivascular parenchyma. Inhibitors of matrix metalloproteinases interrupted this process, suggesting that proteases participate in the remodeling of the endothelium and are required for embolic extravasation. The authors also compared emboli extravasation in younger mice to that of older mice. They found that the rate of emboli extravasation is substantially slower in older mice. In addition, the older mice suffered increased synaptic injury and death following infusion of emboli.
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Loss of patency within the cerebral microvasculature can result in tissue ischemia and cognitive impairment. The observations that microvessels are capable of clearing emboli and that this ability declines with age may improve our understanding of age-related cognitive decline and stroke recovery. That similar age-related processes occur in humans will need to be demonstrated. In addition, the effect of impaired embolic translocation on neuronal damage will need to be more clearly defined. Nonetheless, these studies elegantly demonstrate an unexpected function of the cerebral microvasculature. As the innovative imaging techniques used to make these observations come into wider use, we will likely find out whether this function is observed in other microvascular beds or whether it is a unique feature of cerebral endothelium.
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