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Am J Physiol Cell Physiol (May 31, 2006). doi:10.1152/ajpcell.00639.2005
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Submitted on December 20, 2005
Accepted on May 22, 2006

Peptides based on {alpha}V-Binding Domains of Erythrocyte ICAM-4 Inhibit Sickle Red Cell-endothelial Interactions and Vaso-Occlusion in the Microcirculation

Dhananjaya K Kaul1*, Xiao-du Liu1, Xiaoqin Zhang1, Tosti Mankelow2, Stephen Parsons2, Frances Spring2, Xiuli An3, Mohandas Narla3, David Anstee2, and Joel A Chasis4

1 Medicine, Albert Einstein College of Medicine, Bronx, New York, United States
2 National Blood Service, Bristol Institute for Transfusion Sciences, Bristol, United Kingdom
3 New York Blood Center, New York, New York, United States
4 Life Sciences, University of California, Lawrence Berkeley National Laboratory, Berkeley, California, United States

* To whom correspondence should be addressed. E-mail: kaul{at}aecom.yu.edu.

Growing evidence shows that adhesion molecules on sickle erythrocytes interact with vascular endothelium leading to vaso-occlusion. Erythrocyte intercellular adhesion molecule-4 (ICAM-4) binds {alpha}V integrins, including {alpha}V{beta}3 on endothelial cells. To explore the contribution of ICAM-4 to vascular pathology of sickle cell disease, we tested the effects of synthetic peptides, FWV and ATSR, based on {alpha}V-binding domains of ICAM-4 and capable of inhibiting ICAM-4/ {alpha}V binding in vitro. For these studies we utilized an established ex vivo microvascular model system that enables intravital microscopy and quantitation of adhesion under shear flow. In this model, the use of platelet-activating factor (PAF) that causes endothelial oxidant generation and endothelial activation, mimicked physiological states known to occur in sickle cell disease. Infusion of sickle erythrocytes into PAF treated ex vivo rat mesocecum vasculature produced pronounced adhesion of erythrocytes; small-diameter venules were sites of maximal adhesion and frequent blockage. Both FWV and ATSR peptides markedly decreased adhesion and no vessel blockage was observed with either of the peptides, resulting in improved hemodynamics. ATSR also inhibited adhesion in unactivated microvasculature. While infused fluoresceinated ATSR colocalized with vascular endothelium, pretreatment with function blocking antibody to {alpha}V{beta}3 integrin markedly inhibited this interaction. Our data strengthen the thesis that ICAM-4 on sickle erythrocytes binds endothelium via {alpha}V{beta}3 and that this interaction contributes to vaso-occlusion. Thus, peptides or small molecule mimetics of ICAM-4 may have therapeutic potential.




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