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This Article Full Text Full Text (PDF) All Versions of this Article: 291/5/C922    most recent 00639.2005v2 00639.2005v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (15) Citing Articles via Google Scholar Google Scholar Articles by Kaul, D. K. Articles by Chasis, J. A. Search for Related Content PubMed PubMed Citation Articles by Kaul, D. K. Articles by Chasis, J. A.

VASCULAR BIOLOGY

Peptides based on V-binding domains of erythrocyte ICAM-4 inhibit sickle red cell-endothelial interactions and vaso-occlusion in the microcirculation

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

Submitted 20 December 2005 ; accepted in final form 22 May 2006

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 V-integrins, including V3 on endothelial cells. To explore the contribution of ICAM-4 to vascular pathology of sickle cell disease, we tested the effects of synthetic peptides, V(16)PFWVRMS (FWV) and T(91)RWATSRI (ATSR), based on V-binding domains of ICAM-4 and capable of inhibiting ICAM-4 and 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, which causes endothelial oxidant generation and endothelial activation, mimicked physiological states known to occur in sickle cell disease. Infusion of sickle erythrocytes into platelet-activating factor-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. Although infused fluoresceinated ATSR colocalized with vascular endothelium, pretreatment with function-blocking antibody to V3-integrin markedly inhibited this interaction. Our data strengthen the thesis that ICAM-4 on sickle erythrocytes binds endothelium via V3 and that this interaction contributes to vaso-occlusion. Thus peptides or small molecule mimetics of ICAM-4 may have therapeutic potential.

sickle cell disease; intercellular adhesion molecule-4; V3-integrin; peripheral resistance unit; endothelium; erythrocytes

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