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A role for activated endothelial cells in red blood cell clearance: implications for vasopathology

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  • Marcel H A M Fens, Department of Clinical Chemistry and Hematology, Laboratory for Red Blood Cell Research, University Medical Center Utrecht, Holland
  • Richard van Wijk, Department of Clinical Chemistry and Hematology, Laboratory for Red Blood Cell Research, University Medical Center Utrecht, Holland
  • Grietje Andringa, Department of Clinical Chemistry and Hematology, Laboratory for Red Blood Cell Research, University Medical Center Utrecht, Holland
  • Karlijn L van Rooijen, Department of Clinical Chemistry and Hematology, Laboratory for Red Blood Cell Research, University Medical Center Utrecht, Holland
  • Hilde M Dijstelbloem, Department of Clinical Chemistry and Hematology, Laboratory for Red Blood Cell Research, University Medical Center Utrecht, Holland
  • Jan Trige Rasmussen
  • Karen M K de Voohgt, Department of Clinical Chemistry and Hematology, Laboratory for Red Blood Cell Research, University Medical Center Utrecht, Holland
  • Raymond M Schiffelers, Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences (UIPS), Utrecht University, Holland
  • Carlo A J M Gaillard, Department of Nephrology, VU University Medical Center, Amsterdam, Holland
  • Wouter W van Solinge, Department of Clinical Chemistry and Hematology, Laboratory for Red Blood Cell Research, University Medical Center Utrecht, Holland
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 αv-integrin. Phagocytosis via the phosphatidylserine-lactadherin-αv-integrin pathway is the acknowledged route for removal of apoptotic innate cells by phagocytes.

Design and 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.
OriginalsprogEngelsk
TidsskriftHaematologica
Vol/bind97
Nummer4
Sider (fra-til)500-508
Antal sider9
ISSN0390-6078
DOI
StatusUdgivet - 1 apr. 2012

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