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(Circulation. 2001;103:1906.)
© 2001 American Heart Association, Inc.

Basic Science Reports

Selective _vß₃-Receptor Blockade Reduces Macrophage Infiltration and Restenosis After Balloon Angioplasty in the Atherosclerotic Rabbit

Gregory G. Bishop, MD; John A. McPherson, MD; John M. Sanders, BS; Sean E. Hesselbacher, BS; Michael J. Feldman, BS; Coleen A. McNamara, MD; Lawrence W. Gimple, MD; Eric R. Powers, MD; Shaker A. Mousa, PhD; Ian J. Sarembock, MB, ChB, MD

From the University of Virginia, Charlottesville, Va (G.G.B., J.A.M., J.M.S., S.E.H., M.J.F., C.A.M., L.W.G., E.R.P., I.J.S.), and DuPont Pharmaceutical Company, Wilmington, Del (S.A.M.).

Correspondence to Ian J. Sarembock, MD, Cardiovascular Division, University of Virginia Health System, Box 158, Charlottesville, VA 22908. E-mail ijs4s{at}virginia.edu

	Abstract

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Background—_vß₃-Integrin receptors are upregulated in atherosclerotic arteries and play a key role in smooth muscle cell and possibly inflammatory cell migration. We hypothesized that after balloon angioplasty (BA) of atherosclerotic arteries, selective inhibition of the _vß₃-receptor by XT199, a small-molecule, non–peptide-selective _vß₃-receptor antagonist, would reduce restenosis.

Methods and Results—After induction of focal atherosclerosis, rabbits underwent femoral BA and received XT199 (2.5 mg/kg IV bolus plus 2.5 mg · kg^-1 · d^-1 IV; n=19) or vehicle (n=20) for 14 days. At 28 days after BA, the XT199 group had a larger lumen (0.75±0.26 versus 0.57±0.20 mm², P=0.03) and a smaller neointimal area (0.49±0.18 versus 0.68±0.25 mm², P=0.01) than the vehicle group. Angiographic analysis confirmed a 30% to 40% reduction in restenosis. Arteries harvested at 28 days after BA did not show a reduction in intima plus media smooth muscle cell content but did show a 50% reduction in macrophage cell density in the XT199 group (716±452 versus 1458±989 cells/mm², P<0.006). Neovessel density at 28 days was also reduced (23±42 versus 58±46 vessel cross sections/mm², P<0.02). Early after BA (ie, 3 to 7 days), there was a decrease in intracellular adhesion molecule-1 and vascular cell adhesion molecule-1 expression, indicative of a reduction in vascular cell activation.

Conclusions—Selective _vß₃-receptor blockade for 14 days after BA in the focally atherosclerotic rabbit significantly reduced restenosis and limited macrophage infiltration and neovascularization in the vessel wall.

Key Words: restenosis • angioplasty • inflammation • drugs

	Introduction

Top Abstract Introduction Methods Results Discussion References

 
Blockade of the _vß₃-integrin receptor may be important in attenuating restenosis after balloon angioplasty (BA) of atherosclerotic arteries. Previous in vitro studies suggest that _vß₃-receptors are important in cell-cell and cell-matrix communication and play a key role in smooth muscle (SMC),^{1 2} endothelial,³ and inflammatory cell migration.⁴ These receptors may also play a role in thrombin-induced SMC proliferation,⁵ production of latent transforming growth factor (TGF)-ß,^{6 7} angiogenesis,⁸ apoptosis,⁷ and activation and localization of matrix metalloproteinases (MMP-2).⁷

Restenosis in atherosclerotic arteries involves multiple mechanisms, including early thrombotic and inflammatory responses, SMC proliferation, and extracellular matrix production.^{9 10} Because _vß₃-receptor inhibition may affect many of these processes, we hypothesized that selective inhibition at the time of BA would attenuate restenosis in the focally atherosclerotic rabbit. A second hypothesis was that _vß₃-receptor inhibition would reduce SMC content as well as the inflammatory response. Therefore, we compared histological and angiographic indices of restenosis and SMC, T-cell, and macrophage content in balloon-injured atherosclerotic rabbits treated with XT199 versus vehicle.

	Methods

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_vß₃-Integrin Receptor Antagonist
XT199 [3-(3-(3-(4,5-dihydroimidazol 2-ylamino) propyloxylisoxazol-5-yl) carbonylamino)-2-(phenylsulfonylamino) propionic acid] is a small-molecule, non–peptide-selective _vß₃-receptor antagonist (DuPont Pharmaceuticals Co, Wilmington, Del). In vitro assays specific for adhesion mediated by _vß₃ (rabbit SMC/fibrinogen), _IIbß₃ (rabbit platelet aggregation), _vß₅ (rabbit SMC to vitronectin), and ₅ß₁ (rabbit SMC to biotinylated fibronectin) were performed by methods described previously.^{11 12} All results are reported as the concentration required to inhibit 50% binding (IC₅₀) and are the mean of 3 experiments.

In Vivo Studies
All procedures were done under sterile conditions and general anesthesia (ketamine 50 mg/kg and xylazine 5 mg/kg). This project complied with the procedures approved by the University of Virginia Animal Research Committee.

Focal femoral atherosclerosis was induced in New Zealand White male rabbits by air desiccation injury and a 4-week diet of 0.5% cholesterol and 6% peanut oil, as described previously.¹³ Four weeks later, rabbits underwent bilateral femoral artery BA, including angiography before and after the procedure.¹³ All rabbits received heparin 600 U IV to prevent catheter thrombosis.¹³ Before BA, rabbits were randomly assigned to either XT199 (2.5 mg/kg IV bolus before BA followed by 2.5 mg · kg^-1 · d^-1 IV by osmotic pump for 14 days) or vehicle. Four weeks later, angiography was repeated, and animals were killed by an overdose of sodium pentobarbital (50 mg/kg). Femoral arteries were paraffin embedded and stained by modified Russell-Movat pentachrome stain.¹⁴ A subset of rabbits randomized to either XT199 or vehicle were killed before and at 1, 3, 7, and 14 days after BA (n=5 per time point per group). Femoral arteries were perfused with Dulbecco’s medium at 100 mm Hg, immediately excised, and frozen at -70°C.

Data Analysis
Quantitative Histomorphometry
Measurements of lumen, intima, media, and total vessel area (area bounded by the external elastic lamina [EEL]) were made from paraffin-embedded arteries and results reported as the mean of 3 sections per vessel.¹⁴ The injury score of each artery was assessed with the following scale: 0, intact internal elastic lamina (IEL); 1, lacerated IEL, compression of media; 2, lacerated IEL and media; and 3, large transluminal laceration including disruption of the EEL.¹⁴

Quantitative Angiography
Angiograms were analyzed with a Sony Cardiac Analysis and Review Station (SME-3500 version). Minimal luminal diameter (MLD) was measured before angioplasty (MLD_preBA), 10 minutes after angioplasty (MLD_postBA), and at 28 days (MLD_28d) using the location of initial stenosis in relation to a bony landmark. Late loss was defined as MLD_postBA minus MLD_28d and late loss index as (MLD_postBA-MLD_28d)/(MLD_postBA-MLD_preBA).

Immunohistochemistry
Paraffin-embedded sections were stained with the following antibodies: HHF-35, a mouse monoclonal anti-human -actin, 0.3 µg/mL (Enzo Diagnostics); RAM-11, mouse monoclonal anti-rabbit macrophage, 1.2 µg/mL (Dako Corp)¹⁴ ; polyclonal goat anti-rabbit T cell, 4 µg/mL (Accurat Chem)¹⁴ ; and polyclonal goat anti-mouse PECAM-1 (platelet and endothelial cell adhesion molecule-1), 1 µg/mL (Santa Cruz Biotechnology, Inc).¹⁵ Before labeling with T-cell or PECAM-1 antibodies, arterial tissue underwent microwave antigen retrieval (Vector Labs). Macrophage, T-cell, and neovessel densities were measured manually in each artery at the point of maximal plaque burden by a blinded observer using an Olympus BH-2 microscope at 400x.¹⁶ As a result of high cell density, SMC density was determined with automated cell-counting software (Image Pro, version 5.0; Media Cybernetics).

On frozen sections, the following antibodies were used: LM609, a mouse monoclonal anti-human _vß₃-integrin, 10 µg/mL (Chemicon International Inc)⁸ ; mouse anti-human osteopontin, 2.4 µg/mL (University of Iowa Hybridoma Bank)¹⁷ ; EMR 1a/212D, a monoclonal anti-rabbit vitronectin (ascites fluid, 1:4000, Dr Tatsuya Takano, Teikyo University, Japan)¹⁸ ; RAM-11, 0.03 µg/mL; Rb1/9 and Rb2/3, mouse monoclonal anti-rabbit ICAM-1 (intracellular adhesion molecule-1) and VCAM-1 (vascular cell adhesion molecule-1) antibodies (tissue culture supernatant, 1:10, Dr Myron Cybulsky, University of Toronto)¹⁰ ; and a goat polyclonal anti-rabbit MCP-1 (monocyte chemotactic protein-1) antibody, 5 µg/mL (Dr Teizo Yoshimura, National Cancer Institute, Frederick, Md).¹⁹ A Vectastain Elite ABC kit (Vector Labs) was used to detect primary antibodies, and DAB (DAKO) was used for visualization. Appropriate controls were performed with an isotype control or omission of the primary antibody. Receptor/ligand expression was determined by the percentage of positive staining within the vessel wall with Image Pro software.²⁰

Statistical Analysis
Data are reported as mean±SD. Angiographic and histopathological differences were analyzed by a 2-tailed Student’s t test. For nonparametric data, ie, injury score, a 2-tailed Mann-Whitney U test was performed. A value of P0.05 was considered significant. The slope and intercept of the regression equations were compared with the "comp means" t test from the RS-1 statistical package.

	Results

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XT199 Selectively Inhibits vß₃-Receptor In Vitro
The IC₅₀ of XT199 to inhibit _vß₃-mediated rabbit SMC adhesion to fibrinogen in vitro was 0.05 µmol/L. The IC₅₀ to inhibit platelet aggregation (_IIbß₃-mediated) was >10 µmol/L. In assays specific for _vß₅- and ₅ß₁-mediated adhesion, the IC₅₀ was 0.5 and >10 µmol/L, respectively.

XT199 and Plasma Cholesterol Levels
Plasma levels of XT199 were 0.43±0.53 and 0.43±0.31 µmol/L at 7 and 14 days, respectively, exceeding the in vitro IC₅₀ for _vß₃-mediated adhesion of rabbit SMCs to fibrinogen in all rabbits. After 4 weeks of a 0.5% cholesterol diet, both treatment groups had similar total cholesterol levels (XT199 223±128 mg/dL, vehicle 265±169 mg/dL; P=0.51).

Temporal Expression of the _vß₃-Receptor and Its Ligands
Before BA, expression of _vß₃-receptor and its ligands, vitronectin and osteopontin, occurred within the atherosclerotic plaque (Figure 1). In a prior human heart transplant study,²¹ _vß₃-receptor was present in both normal and atherosclerotic arteries. In the present study, _vß₃-expression was significantly increased at 3 and 7 days after BA. Vitronectin expression was increased at 3 days and persisted to 14 days after BA (Figure 1). Osteopontin expression did not increase after BA (data not shown).

View larger version (52K): [in this window] [in a new window]   Figure 1. vß3-Receptor (A) and vitronectin density (D) in intima and media of atherosclerotic rabbit femoral arteries before BA and at 3, 7, 14, and 28 days after BA. Representative photomicrographs of arterial cross sections stained with monoclonal anti-vß3-receptor antibody, LM609, before BA (B) and 7 days after BA (C). Vitronectin expression, detected by EMR1a/212D-positive staining, before BA (E) and 7 days after BA (F). Note that vß3-integrin receptor and vitronectin densities were elevated between 3 and 7 days (P<0.05), respectively.

Histology at 28 Days
Mean injury scores were similar in the XT199 (n=19; 1.99±0.64) and vehicle groups (n=20; 2.17±0.72) and consistent with severe arterial injury (Table). Lumen area was larger (0.75±0.29 versus 0.57±0.20 mm², P<0.03) and plaque area smaller (0.49±0.18 versus 0.68±0.25 mm², P<0.01) in the XT199 versus vehicle group, respectively. The media and vessel (EEL) areas were not different in the 2 groups (Table). To assess adaptive remodeling, a regression analysis of vessel size versus plaque size was performed.²² There was a good correlation in both the XT199 and vehicle groups (Figure 2), and the slope and intercept of the regression equations were not different, suggesting that adaptive remodeling was not appreciably affected by _vß₃-receptor blockade.

View this table: [in this window] [in a new window]   Table 1. Histological and Angiographic Results 28 Days After BA

View larger version (16K): [in this window] [in a new window]   Figure 2. Regression analysis of plaque area vs vessel size (EEL area) in arteries harvested 28 days after BA and randomized to XT199 or vehicle. XT199 (n=56), r=0.64, P<1.0E–06, y=0.99x+1.09. Vehicle (n=52), r=0.82, P<1.0E–12, y=1.26x+0.77. Slope and intercept were not significantly different.

Immunohistochemistry at 28 Days
Intima plus media -actin–positive cell densities were similar in the XT199 (n=19; 2956±970 cells/mm²) and vehicle groups (n=19; 2536±764 cells/mm²; P=0.17) (Figures 3A, 4A, and 4B). However, macrophage density was significantly decreased by XT199 treatment (716±452 versus 1458±990 cells/mm², P<0.007) (Figures 3A, 4C, and 4D). Peripheral monocyte count was similar at 7 days after therapy (XT199 0.67±0.29 versus vehicle 0.50±0.1 k/uL, P=0.43). T-cell density was not significantly different (Figure 3A).

View larger version (12K): [in this window] [in a new window]   Figure 3. A, SMC, macrophage (M), and T-cell density (cells/mm2) at 28 days after BA in XT199 (n=19) and vehicle (n=19) groups. XT199 group had 51% reduction in macrophage density (P<0.007). B, Neovessel density (cross sections/mm2) was reduced by 60% at 28 days after BA in XT199-treated group.

View larger version (132K): [in this window] [in a new window]   Figure 4. Representative photomicrographs of arterial cross sections at 28 days after BA in XT199-treated and vehicle groups stained for -actin–positive SMCs (A and B) and adjacent sections stained for macrophages (RAM-11) (C and D), magnification x40. E and F, Endothelium-lined neovessels (positive PECAM-1 staining) in XT199- and vehicle-treated groups from representative macrophage-rich sections designated in 4C and 4D, magnification x400.

PECAM-1–positive neovessels in both the intima and media were decreased significantly in the XT199 group (23±36 versus 58±46 vessel cross sections/mm², P<0.02; Figures 3B, 4E, and 4F). The neovessels tended to localize to regions containing large pockets of macrophages.

Immunohistochemistry at 7 Days
To further investigate the effect of _vß₃-receptor blockade on the early inflammatory response after balloon injury, rabbits randomized to either XT199 or vehicle were killed before and at 3, 7, or 14 days after BA. Macrophage infiltration into the vessel increased by 7 days after BA (Figure 5A). Macrophage density was reduced at both 7 days (280±136 versus 754±174 cells/mm², P<0.002) and 14 days (371±71 versus 693±188 cells/mm², P<0.03) in the XT199 group.

View larger version (18K): [in this window] [in a new window]   Figure 5. Time course of macrophage accumulation (cells/mm2) (A), ICAM-1 (B), VCAM-1 (C), and MCP-1 (D) expression (pixel density) in XT199- versus vehicle-treated arteries before BA (n=6) and at 3 (n=5), 7 (n=6), and 14 (n=5) days after BA. Note the significant increase in macrophage density and ICAM-1 and VCAM-1 expression by 3 to 7 days after BA. XT199 significantly reduced macrophage density and ICAM-1 and VCAM-1 expression at early time points. MCP-1 expression was present before BA, unchanged after BA, and not affected by XT199 treatment.

ICAM-1 and VCAM-1 were increased by 3 days and returned to near baseline levels at 14 days after BA. ICAM-1 and VCAM-1 expression were reduced at both 3 and 7 days in the XT199-treated group (Figure 5B and 5C). MCP-1, a potent macrophage chemoattractant found in abundance in atherosclerotic arteries,¹⁹ was expressed in the atherosclerotic wall before BA with no appreciable increase in expression in either group after BA (Figure 5D).

Angiography at 28 Days
In both groups, the MLD_postBA was similar and significantly larger than the MLD_preBA (Table). MLD_28d was larger in the XT199 group (1.17±0.27 versus 0.96±0.32 mm, P<0.03). Both late loss and late loss index were significantly less in the XT199 group (0.39±0.26 versus 0.57±0.28 mm, P<0.05 and 0.91±0.52 versus 1.51±0.70, P<0.008, respectively).

	Discussion

Top Abstract Introduction Methods Results Discussion References

 
Selective _vß₃-receptor inhibition for 14 days after BA in the hypercholesterolemic, focally atherosclerotic rabbit resulted in a 28% reduction in intima area and a 33% increase in lumen size, with no effect on vascular remodeling. These effects were confirmed by serial angiographic analysis. Our findings extend the observations of others in nonatherosclerotic animals.^{1 7 12} However, the arterial response to injury may be quite different in atherosclerotic versus nonatherosclerotic arteries secondary to differences in vascular wall composition (ie, lipid, inflammatory cell, and extracellular matrix) at the time of injury.⁹ In some nonatherosclerotic animal studies,^{1 2} but not all,⁷ _vß₃-receptor inhibition at the time of balloon injury was thought to limit the arterial response to injury by inhibiting SMC migration. In the present study, we did not find a significant reduction in SMC content, but we did find a rather striking 50% reduction in macrophage content at 28 days. Macrophages have been found to be more abundant when restenosis complicates arterial intervention in human arteries.²³ They are rich sources of metalloproteinases,²⁴ inflammatory cytokines, and growth factors.²⁵ It is possible that by reducing macrophage infiltration, the vascular wall pool of cytokines (and growth factors) is reduced, resulting in attenuation of the chronic arterial response to injury characteristic of restenosis.⁹

The reduction in macrophages could have resulted from alterations in cellular adhesion and/or chemotactic factor expression. ICAM-1 and VCAM-1 are expressed on vascular cells after injury, are recognized by counterreceptors on mononuclear cells, and are important in leukocyte recruitment.¹⁰ We found a significant reduction in early ICAM-1 and VCAM-1 expression in the group treated with XT199. Whether this is a direct effect on expression or just a marker of reduced inflammatory activity is unknown. Other investigators⁴ have shown that _vß₃-receptor activation modulates _Lß₂ integrin-dependent monocyte adhesion and migration on ICAM-1, facilitating endothelial transmigration. Additionally, inhibition of _vß₃-receptors on macrophages could reduce PECAM-1–mediated leukocyte endothelial adhesion, because studies suggest that PECAM-1 is a ligand for the _vß₃-receptor.²⁶ Other potential mechanisms include inhibition of macrophage adhesion to extracellular matrix, as shown in the rat wound-healing model, when infiltration was reduced by 60% with an anti-osteopontin antibody.²⁷ MCP-1 expression, important in monocyte chemotaxis,¹⁹ was not attenuated by _vß₃-receptor inhibition in the present study. Other investigators have reported that TGF-ß expression, also important in monocyte chemotaxis,²⁸ is attenuated by _vß₃-receptor inhibition.⁶ Future studies are needed to elucidate which of several potential mechanisms is operative in reducing macrophage recruitment by inhibition of the _vß₃-receptor.

We also a found a significant reduction in neovascularization in the group treated with XT199. In an arthritis model, _vß₃-receptor inhibition reduced neovascularization, possibly by an increase in endothelial cell apoptosis.⁸ In humans, an association of increased neovascularization and macrophage infiltration in unstable coronary plaques²⁹ and restenotic arteries³⁰ has been described. Proposed mechanisms include contributions by macrophages and monocytes to formation of neovessels by release of angiogenic factors (basic fibroblast growth factor) or growth factors (TGF-ß) that promote the expression of angiogenic factors (urokinase plasmin activator or vascular endothelial growth factor).³¹ Alternatively, neovascularization may result in increased cell adhesion molecule expression and leukocyte recruitment.²⁹

Clinical trials using the nonspecific ß₃-receptor inhibitor abciximab report a decrease in adverse cardiac events, including death and myocardial infarction, at 6 and 12 months after percutaneous coronary intervention.³² The exact mechanism for this benefit is unknown. In the context of our results, one might speculate that blockade of the _vß₃-receptor by abciximab³³ may decrease inflammatory cell infiltration and neovascularization after percutaneous intervention, thus improving plaque stability and reducing adverse cardiac events.

Limitations of this study include the inability to measure SMC migration in our second injury model after balloon injury because the resulting neointima is composed of both migrating SMCs and SMCs present in the atherosclerotic lesion before balloon injury.³⁴ Another limitation is the possibility that the beneficial effects of XT199 were mediated through blockade of integrins such as the _IIbß₃. However, plasma levels of XT199 were one tenth of the IC₅₀ for inhibition of platelet aggregation via the _IIbß₃-integrin, and a prior study in rabbits,³⁵ which used a specific inhibitor of this receptor, was negative.

In summary, we have shown that specific _vß₃-receptor inhibition with XT199 at therapeutic plasma concentration for 14 days reduced histological and angiographic measures of restenosis without an effect on remodeling in the focally atherosclerotic rabbit. This beneficial effect was associated with a marked 50% to 60% reduction in macrophage content, neovascularization, and early inflammatory marker expression. Taken together, these observations suggest that specific _vß₃-receptor blockade at the time of vascular injury in atherosclerotic arteries favorably modulates the response to injury, in part through a novel effect on the inflammatory system.

	Acknowledgments

 
This study was supported in part by an American Heart Association National Grant-in-Aid (No. 95009480, Dr Sarembock) and NIH training grant HL07355 (Dr Bishop). We thank the vivarium staff of the Department of Comparative Medicine at the University of Virginia for their excellent animal care.

Received June 15, 2000; revision received October 27, 2000; accepted October 27, 2000.

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