Peptides based on alphaV-binding domains of erythrocyte ICAM-4 inhibit sickle red cell-endothelial interactions and vaso-occlusion in the microcirculation.
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.
Kaul
Dhananjay K
DK
Dept. of Medicine, Albert Einstein College of Medicine, Bronx, NY 10461, USA. kaul@aecom.yu.edu
Liu
Xiao-du
XD
Zhang
Xiaoqin
X
Mankelow
Tosti
T
Parsons
Stephen
S
Spring
Frances
F
An
Xiuli
X
Mohandas
Narla
N
Anstee
David
D
Chasis
Joel Anne
JA
D000755:Anemia, Sickle Cell / Q000473:pathology*; D000818:Animals; D002448:Cell Adhesion / Q000187:drug effects; D015815:Cell Adhesion Molecules / Q000737:chemistry* / Q000378:metabolism; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects*; D004913:Erythrocytes, Abnormal / Q000187:drug effects* / Q000473:pathology; D006801:Humans; D066298:In Vitro Techniques; D039564:Integrin alphaV / Q000378:metabolism*; D008833:Microcirculation / Q000187:drug effects / Q000473:pathology*; D010455:Peptides / Q000737:chemistry / Q000494:pharmacology*; D010972:Platelet Activating Factor / Q000494:pharmacology; D011485:Protein Binding / Q000187:drug effects; D017434:Protein Structure, Tertiary; D021381:Protein Transport / Q000187:drug effects; D051381:Rats; D012044:Regression Analysis
D015815:Cell Adhesion Molecules; D039564:Integrin alphaV; D010455:Peptides; D010972:Platelet Activating Factor