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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.
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Submitted February 26, 2004
Accepted July 13, 2004
The contribution of endothelial cell P-selectin to the microvascular flow of mouse sickle erythrocytes in vivo
Stephen H Embury*, Neil M Matsui, Sahana Ramanujam, Tanya N Mayadas, Constance T Noguchi, Bhalchandra A Diwan, Narla Mohandas, and Anthony T Cheung
Department of Medicine, University of California, San Francisco and San Francisco General Hospital, San Francisco, CA, USA
Department of Pediatrics, University of California, San Francisco and San Francisco General Hospital, San Francisco, CA, USA; Northern California Comprehensive Sickle Cell Center, University of California, San Francisco and San Francisco General Hospital, San Francisco, CA, USA
Department of Medical Pathology, University of California, Davis Medical Center, Sacramento, CA, USA
Department of Pathology, Brigham and Womens Hospital, Harvard Medical School, Boston, MA, USA
Laboratory of Chemical Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA
Basic Research Program, Science Applications International Corp. at Frederick, National Cancer Institute at Frederick, MD, USA
The New York Blood Center, New York, NY, USA
* Corresponding author; email: sembury{at}itsa.ucsf.edu.
Microvascular occlusion in sickle cell disease can be initiated by adhesion of sickle RBC to the endothelium. Our objective in this study was to verify the relevance in vivo of our discovery that sickle RBC adhere abnormally to endothelial P-selectin in vitro. We used computer-assisted intravital microscopy to characterize RBC flow velocities (VRBC) in mice. We found faster VRBC of sickle RBC in P-selectin knockout 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 knockout mice or in control mice pre-treated 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.
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