Microvascular endothelial cells express a phosphatidylserine receptor: a functionally active receptor for phosphatidylserine-positive erythrocytes.
Phosphatidylserine (PS)-positive erythrocytes adhere to endothelium and subendothelial matrix components. While thrombospondin mediates these inter-actions, it is unknown whether PS-associated erythrocyte-endothelial adhesion occurs in the absence of plasma ligands. Using ionophore-treated PS-expressing control HbAA erythrocytes, we demonstrate that PS-positive erythrocytes adhered to human lung microendothelial cells in the absence of plasma ligands, that this adhesion was enhanced following endothelial activation with IL-1alpha, TNF-alpha, LPS, hypoxia, and heme, and that this adhesive interaction was selective to erythrocyte PS. We next explored whether microendothelial cells express an adhesion receptor that recognizes cell surface-expressed PS (PSR) similar to that expressed on activated macrophages. We demonstrate constitutive expression of both PSR mRNA and protein that were up-regulated in a time-dependent manner following endothelial activation. While minimal PSR expression was noted on unstimulated cells, endothelial activation up-regulated PSR surface expression. In antibody-blocking studies, using PS-positive erythrocytes generated either artificially via ionophore treatment of control erythrocytes or from patients with sickle cell disease, we demonstrate that PSR was functional, supporting PS-mediated erythrocyte adhesion to activated endothelium. Our results demonstrate the existence of a novel functional adhesion receptor for PS on the microendothelium that is up-regulated by such pathologically relevant agonists as hypoxia, cytokines, and heme.
Setty
B N Yamaja
BN
Marian Anderson Comprehensive Sickle Cell Anemia Care and Research Center, Department of Pediatrics, Jefferson Medical College, Thomas Jefferson University, Philadelphia, PA 19107, USA. yamaja.setty@jefferson.edu
Betal
Suhita Gayen
SG
D000328:Adult; D002448:Cell Adhesion / Q000502:physiology; D015687:Cell Hypoxia / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism*; D004912:Erythrocytes / Q000166:cytology / Q000378:metabolism*; D005109:Extracellular Matrix / Q000378:metabolism; D005260:Female; D006418:Heme / Q000494:pharmacology; D006441:Hemoglobin A / Q000378:metabolism; D006801:Humans; D053582:Interleukin-1alpha / Q000494:pharmacology; D007476:Ionophores / Q000494:pharmacology; D008024:Ligands; D008070:Lipopolysaccharides / Q000494:pharmacology; D008168:Lung / Q000098:blood supply / Q000166:cytology / Q000378:metabolism*; D008262:Macrophage Activation / Q000187:drug effects / Q000502:physiology; D008264:Macrophages / Q000166:cytology / Q000378:metabolism; D008297:Male; D008833:Microcirculation / Q000378:metabolism; D010718:Phosphatidylserines / Q000037:antagonists & inhibitors / Q000378:metabolism*; D012333:RNA, Messenger / Q000096:biosynthesis; D011956:Receptors, Cell Surface / Q000819:agonists / Q000096:biosynthesis*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology*
D053582:Interleukin-1alpha; D007476:Ionophores; D008024:Ligands; D008070:Lipopolysaccharides; D010718:Phosphatidylserines; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; D014409:Tumor Necrosis Factor-alpha; C408123:phosphatidylserine receptor; C028672:hemoglobin AA; D006418:Heme; D006441:Hemoglobin A