α₄β₁ Integrin (VLA-4) Blockade Attenuates both Early and Late Leukocyte Recruitment and Neointimal Growth following Carotid Injury in Apolipoprotein E (–/–) Mice

Abstract

Background: The α₄β₁ 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.

Cyclic arginine-glycine-aspartic acid peptide inhibits macrophage infiltration of the kidney and carotid artery lesions in apo-E-deficient mice

“…Although inefficient at the aortic root and curvature, the peptide was effective in preventing monocytic infiltration of the injured carotid artery. These data are in good agreement with the recently described upregulation of adhesive partners VLA4 and VCAM-1 in the vasculature of ApoE Ϫ/Ϫ mice 3-7 days after air desiccation injury to carotid arteries and a remarkable efficiency of a neutralizing monoclonal anti-VLA4 antibody, PS/2, in attenuating leukocyte recruitment and neointimal formation (2). The observed selectivity of the RGD effect (significant attenuation of macrophage infiltration of and lipid accumulation in glomeruli and injured carotid artery, with the lesser effect in the aorta) is in good agreement with the predominant distribution of ␣ 4 ␤ 1 -integrin (VLA4) to the renal vasculature and injured vessels (2,7).…”

“…These data are in good agreement with the recently described upregulation of adhesive partners VLA4 and VCAM-1 in the vasculature of ApoE Ϫ/Ϫ mice 3-7 days after air desiccation injury to carotid arteries and a remarkable efficiency of a neutralizing monoclonal anti-VLA4 antibody, PS/2, in attenuating leukocyte recruitment and neointimal formation (2). The observed selectivity of the RGD effect (significant attenuation of macrophage infiltration of and lipid accumulation in glomeruli and injured carotid artery, with the lesser effect in the aorta) is in good agreement with the predominant distribution of ␣ 4 ␤ 1 -integrin (VLA4) to the renal vasculature and injured vessels (2,7). In addition to this distinction, we clearly appreciate that there are multiple other receptors participating in the monocyte-endothelial cell adhesion and transmigration, and their contribution to the process may be insensitive to cRGD peptide, thus reducing its efficacy.…”

siRNA silencing reveals role of vascular cell adhesion molecule-1 in vascular smooth muscle cell migration

“…VCAM-1 is expressed at high levels in injured arteries and in atherosclerotic lesions [7,18]. Using Western blot analysis, we demonstrated the expression of VCAM-1 in the descending aorta of apoE-deficient mice when fed chow and Western diets [19].…”

“…VCAM-1 interacts with the integrin α 4 β 1 (very late-acting antigen 4 ) that is constitutively expressed on the surface of leukocytes. Blockade of the VCAM-1/VLA-4 pathway reduces monocyte adhesion and infiltration and neointimal formation after arterial injury [6,7]. VCAM-1 domain 4-deficiency markedly reduced arterial VCAM-1 expression, monocyte adherence in the aortic root, and fatty streak formation in apolipoprotein E-deficient mice [8].…”

“…VCAM-1 domain 4-deficiency markedly reduced arterial VCAM-1 expression, monocyte adherence in the aortic root, and fatty streak formation in apolipoprotein E-deficient mice [8]. Recent studies have shown that VCAM-1 is required for accumulation of SMC in the neointima in the mouse injury model [7] and VLA-4 is expressed on SMC [9], thus suggesting a possibility that VCAM-1 may act directly on SMC in addition to inflammatory cells.…”