Alpha4beta1 integrin (VLA-4) blockade attenuates both early and late leukocyte recruitment and neointimal growth following carotid injury in apolipoprotein E (-/-) mice.
BACKGROUND
The alpha(4)beta(1) integrin (VLA-4) supports rolling and firm adhesion of leukocytes to inflamed tissues via ligation of VCAM-1 or fibronectin expressed on the activated endothelium. We tested the hypothesis that VLA-4 mediates leukocyte recruitment and neointimal growth after arterial injury in the atherosclerosis-prone apolipoprotein E (ApoE)-deficient mouse.


METHODS
ApoE (-/-) mice fed a Western diet underwent air desiccation injury, and the expression patterns of VLA-4 and VCAM-1 were determined by immunohistochemistry (IHC). To determine the effect of targeted VLA-4 blockade on leukocyte recruitment and neointimal growth, ApoE (-/-) mice received an intraperitoneal injection of a VLA-4 neutralizing monoclonal antibody (PS/2) at the time of injury alone or over a prolonged administration course. Additional mice received an isotype control antibody.


RESULTS
IHC demonstrated a marked increase in VLA-4 expression 7 days following injury. Prolonged administration of PS/2 resulted in a 72% reduction (p < 0.02) in neointimal growth 28 days following injury. IHC revealed a marked 95% reduction in neutrophil recruitment at 7 days and a 48% reduction in macrophage recruitment 28 days following injury with prolonged PS/2 administration.


CONCLUSIONS
Prolonged VLA-4 blockade reduces leukocyte recruitment and neointimal growth following air desiccation injury in ApoE (-/-) mice. These findings demonstrate an important role for VLA-4 in the response to arterial injury.
Barringhaus
Kurt G
KG
Department of Medicine, Cardiovascular Division, University of Virginia Health System, Charlottesville 22908-0158, USA.
Phillips
J William
JW
Thatte
Jayant S
JS
Sanders
John M
JM
Czarnik
Ann C
AC
Bennett
Daniel K
DK
Ley
Klaus F
KF
Sarembock
Ian J
IJ
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D001057:Apolipoproteins E / Q000172:deficiency*; D020212:Carotid Artery Injuries / Q000097:blood / Q000209:etiology / Q000378:metabolism* / Q000473:pathology*; D003890:Desiccation; D005260:Female; D005434:Flow Cytometry; D066298:In Vitro Techniques; D039041:Integrin alpha4beta1 / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000378:metabolism; D007958:Leukocyte Count; D007962:Leukocytes / Q000473:pathology*; D008055:Lipids / Q000097:blood; D008264:Macrophages / Q000187:drug effects / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020556:Neutrophil Infiltration / Q000187:drug effects; D013997:Time Factors; D017539:Tunica Intima / Q000473:pathology*; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism
D000911:Antibodies, Monoclonal; D001057:Apolipoproteins E; D039041:Integrin alpha4beta1; D008055:Lipids; D019010:Vascular Cell Adhesion Molecule-1