Microembolus clearance through angiophagy is an auxiliary mechanism preserving tissue perfusion in the rat brain
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2020) 8:195
Open Access
RESEARCH
Microembolus clearance through angiophagy is an auxiliary mechanism preserving tissue perfusion in the rat brain Anne‑Eva van der Wijk1† , Theodosia Georgakopoulou1† , Jisca Majolée2 , Jan S. M. van Bezu2, Miesje M. van der Stoel3 , Bert J. van het Hof4, Helga E. de Vries4 , Stephan Huveneers3 , Peter L. Hordijk2 , Erik N. T. P. Bakker1 and Ed van Bavel1,5*
Abstract Considering its intolerance to ischemia, it is of critical importance for the brain to efficiently process microvascular occlusions and maintain tissue perfusion. In addition to collateral microvascular flow and enzymatic degradation of emboli, the endothelium has the potential to engulf microparticles and thereby recanalize the vessel, through a process called angiophagy. Here, we set out to study the dynamics of angiophagy in relation to cytoskeletal remod‑ eling in vitro and reperfusion in vivo. We show that polystyrene microspheres and fibrin clots are actively taken up by (brain) endothelial cells in vitro, and chart the dynamics of the actin cytoskeleton during this process using live cell imaging. Whereas microspheres were taken up through the formation of a cup structure by the apical endothelial membrane, fibrin clots were completely engulfed by the cells, marked by dense F-actin accumulation surround‑ ing the clot. Both microspheres and fibrin clots were retained in the endothelial cells. Notably, fibrin clots were not degraded intracellularly. Using an in vivo microembolization rat model, in which microparticles are injected into the common carotid artery, we found that microspheres are transported by the endothelium from the microvasculature into the brain parenchyma. Microembolization with microspheres caused temporal opening of the blood–brain bar‑ rier and vascular nonperfusion, followed by microsphere extravasation and restoration of vessel perfusion over time. Taken together, angiophagy is accompanied by active cytoskeletal remodeling of the endothelium, and is an effective mechanism to restore perfusion of the occluded microvasculature in vivo. Keywords: Angiophagy, Cerebral microcirculation, Embolus, Endothelial cells Introduction Although the brain comprises only 2% of the body weight, it is responsible for approximately 20% of the total body’s energy expenditure [24]. Since the brain has no substantial local energy storage, it has a critical need for a constant cerebral blood flow. In order to maintain *Correspondence: [email protected] † Shared first authorship: Anne-Eva van der Wijk and Theodosia Georgakopoulou 5 Department of Biomedical Engineering and Physics, Academic Medical Center, Room L0‑120, 1100 DD Amsterdam, The Netherlands Full list of author information is available at the end of the article
sufficient perfusion to meet its energy demands, the brain has a uniquely organized vascular network. The cerebral cortex is supplied and drained by interconnected pial arteriolar and venular networks, connected through penetrating arterioles and venules with the three-dimensi
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