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Blood, 15 November 2004, Vol. 104, No. 10, pp. 3378-3385. Prepublished online as a Blood First Edition Paper on July 22, 2004; DOI 10.1182/blood-2004-02-0713.
RED CELLS The contribution of endothelial cell P-selectin to the microvascular flow of mouse sickle erythrocytes in vivoFrom the Departments of Medicine and Pediatrics, University of California, San Francisco, and San Francisco General Hospital; Northern California Comprehensive Sickle Cell Center, San Francisco; Department of Medical Pathology, University of California, Davis Medical Center, Sacramento; Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA; Laboratory of Chemical Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD; Basic Research Program, Science Applications International Corporation at Frederick, National Cancer Institute at Frederick, MD; and The New York Blood Center, New York.
Microvascular occlusion in sickle cell disease can be initiated by adhesion of sickle red blood cells (RBCs) to the endothelium. Our objective in this study was to verify the relevance in vivo of our discovery that sickle RBCs adhere abnormally to endothelial P-selectin in vitro. We used computer-assisted intravital microscopy to characterize RBC flow velocity (VRBC) in mice. We found faster VRBC of sickle RBCs in P-selectin knock-out and control mice than in sickle cell mice, which have increased endothelial cell P-selectin expression. Agonist peptide for murine protease-activated receptor-1 (PAR-1), which selectively activates mouse endothelial cells but not platelets, was used to assess the effects of endothelial cell P-selectin on microvascular flow. Suffusion of venules with this agonist stopped flow promptly in normal and sickle mice but not in P-selectin knock-out mice or in control mice pretreated with anti-P-selectin monoclonal antibody or unfractionated heparin (UFH). Agonist-induced slowing of flow was reversed rapidly by suffusion with UFH, provided flow had not already stopped. We conclude that endothelial cell P-selectin contributes to the microcirculatory abnormalities in sickle cell disease and that blocking P-selectin may be useful for preventing painful vasoocclusion in sickle cell disease. (Blood. 2004;104:3378-3385)
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| Copyright © 2004 by American Society of Hematology Online ISSN: 1528-0020 | |||||||||
