title: Angiophagy prevents early embolus washout but recanalizes microvessels through embolus extravasation.
abstract: 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.
authors.affiliation: Department of Neurology, Yale University School of Medicine, New Haven, CT 06510, USA.
authors.forename: Jaime
authors.initials: J
authors.lastname: Grutzendler
authors.forename: Sasidhar
authors.initials: S
authors.lastname: Murikinati
authors.forename: Bennett
authors.initials: B
authors.lastname: Hiner
authors.forename: Lingling
authors.initials: L
authors.lastname: Ji
authors.forename: Carson K
authors.initials: CK
authors.lastname: Lam
authors.forename: Taehwan
authors.initials: T
authors.lastname: Yoo
authors.forename: Shobhana
authors.initials: S
authors.lastname: Gupta
authors.forename: Brian P
authors.initials: BP
authors.lastname: Hafler
authors.forename: Ron A
authors.initials: RA
authors.lastname: Adelman
authors.forename: Peng
authors.initials: P
authors.lastname: Yuan
authors.forename: Guadalupe
authors.initials: G
authors.lastname: Rodriguez
mesh_terms: D000818:Animals; D001921:Brain / Q000098:blood supply; D002560:Cerebrovascular Circulation / Q000502:physiology; D003326:Coronary Circulation; D004617:Embolism / Q000473:pathology*; D005337:Fibrin / Q000737:chemistry; D005342:Fibrinolysis; D005654:Fundus Oculi; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006439:Hemodynamics; D006801:Humans; D007684:Kidney Tubules / Q000098:blood supply; D008168:Lung / Q000098:blood supply; D008264:Macrophages / Q000166:cytology; D051379:Mice; D008822:Mice, Transgenic; D008833:Microcirculation; D017628:Microglia / Q000378:metabolism; D046529:Microscopy, Electron, Transmission; D055806:Microvessels; D009000:Monocytes / Q000166:cytology; D010587:Phagocytosis; D012160:Retina / Q000378:metabolism; D012171:Retinal Vessels / Q000473:pathology*; D013927:Thrombosis
chemical_list: D049452:Green Fluorescent Proteins; D005337:Fibrin