title: A role for activated endothelial cells in red blood cell clearance: implications for vasopathology.
abstract: BACKGROUND
  Phosphatidylserine exposure by red blood cells is acknowledged as a signal that initiates phagocytic removal of the cells from the circulation. Several disorders and conditions are known to induce phosphatidylserine exposure. Removal of phosphatidylserine-exposing red blood cells generally occurs by macrophages in the spleen and liver. Previously, however, we have shown that endothelial cells are also capable of erythrophagocytosis. Key players in the erythrophagocytosis by endothelial cells appeared to be lactadherin and α(v)-integrin. Phagocytosis via the phosphatidylserine-lactadherin-α(v)-integrin pathway is the acknowledged route for removal of apoptotic innate cells by phagocytes.
  
  
  METHODS
  Endothelial cell phagocytosis of red blood cells was further explored using a more (patho)physiological approach. Red blood cells were exposed to oxidative stress, induced by tert-butyl hydroperoxide. After opsonization with lactadherin, red blood cells were incubated with endothelial cells to study erythrophagocytosis and examine cytotoxicity.
  
  
  RESULTS
  Red blood cells exposed to oxidative stress show alterations such as phosphatidylserine exposure and loss of deformability. When incubated with endothelial cells, marked erythrophagocytosis occurred in the presence of lactadherin under both static and flow conditions. As a consequence, intracellular organization was disturbed and endothelial cells were seen to change shape ('rounding up'). Increased expression of apoptotic markers indicated that marked erythrophagocytosis has cytotoxic effects.
  
  
  CONCLUSIONS
  Activated endothelial cells show significant phagocytosis of phosphatidylserine-exposing and rigid red blood cells under both static and flow conditions. This results in a certain degree of cytotoxicity. We postulate that activated endothelial cells play a role in red blood cell clearance in vivo. Significant erythrophagocytosis can induce endothelial cell loss, which may contribute to vasopathological effects as seen, for instance, in sickle cell disease.
authors.affiliation: Department of Clinical Chemistry and Hematology, Laboratory for Red Blood Cell Research, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Marcel H A M
authors.initials: MH
authors.lastname: Fens
authors.forename: Richard
authors.initials: R
authors.lastname: van Wijk
authors.forename: Grietje
authors.initials: G
authors.lastname: Andringa
authors.forename: Karlijn L
authors.initials: KL
authors.lastname: van Rooijen
authors.forename: Hilde M
authors.initials: HM
authors.lastname: Dijstelbloem
authors.forename: Jan T
authors.initials: JT
authors.lastname: Rasmussen
authors.forename: Karen M K
authors.initials: KM
authors.lastname: de Vooght
authors.forename: Raymond M
authors.initials: RM
authors.lastname: Schiffelers
authors.forename: Carlo A J M
authors.initials: CA
authors.lastname: Gaillard
authors.forename: Wouter W
authors.initials: WW
authors.lastname: van Solinge
mesh_terms: D001808:Blood Vessels / Q000378:metabolism / Q000503:physiopathology; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000378:metabolism*; D004907:Erythrocyte Deformability / Q000187:drug effects; D004912:Erythrocytes / Q000187:drug effects / Q000378:metabolism*; D006461:Hemolysis; D006801:Humans; D009996:Osmotic Fragility; D018384:Oxidative Stress; D010587:Phagocytosis / Q000187:drug effects / Q000502:physiology; D010718:Phosphatidylserines / Q000494:pharmacology
chemical_list: D010718:Phosphatidylserines
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