Peptides based on αV-binding domains of erythrocyte ICAM-4 inhibit sickle red cell-endothelial interactions and vaso-occlusion in the microcirculation
| Autor: | Frances A. Spring, David J. Anstee, Narla Mohandas, Tosti J. Mankelow, Dhananjay K. Kaul, Stephen Parsons, Xiaoqin Zhang, Xiao-du Liu, Joel Anne Chasis, Xiuli An |
|---|---|
| Rok vydání: | 2006 |
| Předmět: |
Endothelium
Physiology Erythrocytes Abnormal Anemia Sickle Cell In Vitro Techniques Biology Microcirculation Occlusion Cell Adhesion medicine Animals Humans Platelet Activating Factor Red Cell Cell adhesion molecule Soluble cell adhesion molecules Endothelial Cells Cell Biology Adhesion Integrin alphaV Protein Structure Tertiary Rats Cell biology Protein Transport medicine.anatomical_structure Regression Analysis Peptides Cell Adhesion Molecules Intracellular Protein Binding |
| Zdroj: | American Journal of Physiology-Cell Physiology. 291:C922-C930 |
| ISSN: | 1522-1563 0363-6143 |
| DOI: | 10.1152/ajpcell.00639.2005 |
| Popis: | 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 alphaV-integrins, including alphaVbeta3 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 alphaV-binding domains of ICAM-4 and capable of inhibiting ICAM-4 and alphaV-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 alphaVbeta3-integrin markedly inhibited this interaction. Our data strengthen the thesis that ICAM-4 on sickle erythrocytes binds endothelium via alphaVbeta3 and that this interaction contributes to vaso-occlusion. Thus peptides or small molecule mimetics of ICAM-4 may have therapeutic potential. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|