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Peptides based on alphaV-binding domains of erythrocyte ICAM-4 inhibit sickle red cell-endothelial interactions and vaso-occlusion in the microcirculation.
Am J Physiol Cell Physiol 2006; 291(5):C922-30AJ

Abstract

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.

Authors+Show Affiliations

Dept. of Medicine, Albert Einstein College of Medicine, Bronx, NY 10461, USA. kaul@aecom.yu.eduNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

Language

eng

PubMed ID

16738001

Citation

Kaul, Dhananjay K., et al. "Peptides Based On alphaV-binding Domains of Erythrocyte ICAM-4 Inhibit Sickle Red Cell-endothelial Interactions and Vaso-occlusion in the Microcirculation." American Journal of Physiology. Cell Physiology, vol. 291, no. 5, 2006, pp. C922-30.
Kaul DK, Liu XD, Zhang X, et al. Peptides based on alphaV-binding domains of erythrocyte ICAM-4 inhibit sickle red cell-endothelial interactions and vaso-occlusion in the microcirculation. Am J Physiol, Cell Physiol. 2006;291(5):C922-30.
Kaul, D. K., Liu, X. D., Zhang, X., Mankelow, T., Parsons, S., Spring, F., ... Chasis, J. A. (2006). Peptides based on alphaV-binding domains of erythrocyte ICAM-4 inhibit sickle red cell-endothelial interactions and vaso-occlusion in the microcirculation. American Journal of Physiology. Cell Physiology, 291(5), pp. C922-30.
Kaul DK, et al. Peptides Based On alphaV-binding Domains of Erythrocyte ICAM-4 Inhibit Sickle Red Cell-endothelial Interactions and Vaso-occlusion in the Microcirculation. Am J Physiol, Cell Physiol. 2006;291(5):C922-30. PubMed PMID: 16738001.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Peptides based on alphaV-binding domains of erythrocyte ICAM-4 inhibit sickle red cell-endothelial interactions and vaso-occlusion in the microcirculation. AU - Kaul,Dhananjay K, AU - Liu,Xiao-du, AU - Zhang,Xiaoqin, AU - Mankelow,Tosti, AU - Parsons,Stephen, AU - Spring,Frances, AU - An,Xiuli, AU - Mohandas,Narla, AU - Anstee,David, AU - Chasis,Joel Anne, Y1 - 2006/05/31/ PY - 2006/6/2/pubmed PY - 2006/12/9/medline PY - 2006/6/2/entrez SP - C922 EP - 30 JF - American journal of physiology. Cell physiology JO - Am. J. Physiol., Cell Physiol. VL - 291 IS - 5 N2 - 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. SN - 0363-6143 UR - https://www.unboundmedicine.com/medline/citation/16738001/Peptides_based_on_alphaV_binding_domains_of_erythrocyte_ICAM_4_inhibit_sickle_red_cell_endothelial_interactions_and_vaso_occlusion_in_the_microcirculation_ L2 - http://www.physiology.org/doi/full/10.1152/ajpcell.00639.2005?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -