(Circulation. 1997;96:3587-3592.)
© 1997 American Heart Association, Inc.
Articles |
Intimal Hyperplasia After Balloon Injury Is Attenuated by Blocking Selectins
From the Cardiology Section, Tulane University Medical Center, New Orleans, La.
Correspondence to Alan N. Tenaglia, MD, Tulane University Medical Center, School of Medicine, Department of Medicine, Cardiology Section SL-48, 1430 Tulane Ave, New Orleans, LA 70112-2699. E-mail atenagl{at}tmc.tulane.edu
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Abstract |
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Background Cell adhesion molecules facilitate the adherence of platelets and leukocytes to the vascular endothelium in response to injury. Restenosis after balloon angioplasty is thought to represent the response to vascular injury. The role of cell adhesion in this process is unclear.
Methods and Results This study was performed in New Zealand White rabbits that underwent balloon angioplasty of the iliac artery. Expression of the cell adhesion molecule E-selectin on endothelium was determined by immunohistochemistry and increased at 6 hours with a peak expression 24 to 48 hours after balloon injury, returning to baseline by 1 week. The expression of L-selectin on circulating leukocytes, measured by flow cytometry, was significantly increased at 48 hours, with return to baseline by 1 week. In seven animals, the selectins were blocked with an analogue of sialyl-LewisX given as an IV bolus of 10 mg/kg followed by 2 mg · kg-1 · h-1 IP infusion for 7 days. After 4 weeks, compared with control animals, the study group had a larger lumen area (57.7 versus 44.7 mm2, P<.05), smaller intima area (9.0 versus 19.2 mm2, P<.01), smaller intima/media ratio (0.4 versus 1.0, P<.01), and a smaller percent area stenosis (15.6% versus 34.3%, P<.01).
Conclusions The cell adhesion molecules E-selectin and L-selectin are expressed after balloon injury. Blockade of the selectins has a favorable effect on the response to vascular injury.
Key Words: angioplasty • balloon • adhesion molecules • restenosis
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Introduction |
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Since its introduction in 1977, percutaneous transluminal coronary angioplasty (PTCA) has proved to be a very effective treatment for coronary artery disease.1 However, long-term success is limited by restenosis.2 Although many mechanisms have been proposed to explain the pathophysiology of restenosis,3–5 there is growing evidence that the process involves the normal vascular response to vessel injury.6,7
Cell adhesion molecules (CAMs) are glycoproteins found on formed elements in the blood and on the surface of endothelial cells that facilitate the adhesion of platelets and leukocytes to the vascular endothelium.8–11 Cell adhesion allows leukocytes to locally release a variety of cytotoxic mediators and cytokines. CAMs have been shown to play an important role in other tissue injury models, such as ischemia-reperfusion.12,13 Our group has previously shown that blocking the selectin family of CAMs with an oligosaccharide analogue of sialyl-LewisX (CY-1503, Cytel Corp) significantly reduced myocardial injury after ischemia-reperfusion.14 On the basis of these encouraging results in an ischemia-reperfusion injury model, the present study was undertaken to evaluate the role of CAMs in the response to vascular injury after balloon angioplasty.
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Methods |
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New Zealand White rabbits of either sex, weighing
3 kg, were
used. All procedures were performed under sterile conditions with the
approval of the Institutional Animal Care and Use Committee in
compliance with procedures and methods outlined by the National
Institutes of Health (Guide for the Care and Use of Laboratory
Animals, National Institutes of Health, Bethesda, Md, NIH
publication No. 86–23).
Balloon Injury and Tissue Preparation
All rabbits were anesthetized with ketamine 49
mg/kg IM and xylazine 10 mg/kg IM, with periodic doses of
both agents given to maintain anesthesia. An incision was
made in the right lateral neck to expose the right carotid artery.
Balloon-induced arterial injury was performed as previously
described.15 An arteriotomy was performed, and a
standard 2.5x20-mm balloon catheter was introduced under fluoroscopic
guidance. Heparin 150 U/kg was administered by bolus infusion via an
ear vein. A 0.014-in guidewire was advanced under fluoroscopy to the
distal right femoral artery. The balloon catheter was then advanced
under fluoroscopy to the proximal right iliac artery. Three separate
balloon inflations at 10 atm for 1 minute each with 1 minute between
inflations were performed. The balloon catheter was then removed and
the right carotid artery ligated. The surgical wound was closed
according to standard surgical procedure. Animals were observed for any
signs of postoperative discomfort and treated with butorphanol tartrate
IM if indicated. All rabbits were fed a standard laboratory chow diet
and watched carefully for any signs of infection or other illness.
At various time intervals as discussed below, animals were killed with an overdose of pentobarbital sodium 120 mg/kg by intracardiac injection. Twenty minutes before they were killed, animals were injected with Evans blue dye 50 mg/kg IV to better visualize the previously injured segment of artery. After the animals were killed, iliac arteries were harvested en bloc and the tissue was placed in cold 4% paraformaldehyde for 2 hours, then transferred to 30% sucrose in PBS overnight at 4°C. The next day, tissue was embedded in OCT, snap-frozen in liquid nitrogen, and stored at -80°C. With a cryostat, frozen tissue was then cut into 7-µm slices and mounted on sialinized slides.
Arterial Measurements
Video microscopy and computerized digital image analysis
was performed with the Optimas system (Optimas Corp). For each animal,
eight rings were randomly chosen in the area of balloon injury, and
measurements were made by two independent observers and averaged.
Measurements were made of the area within the external elastic lamina
(EEL area), the area within the internal elastic lamina (IEL area), and
the lumen area. Other areas were calculated as follows: media area=EEL
area-IEL area; intima area=IEL area-lumen area; intima/media
ratio=intima area/media area; and percent area stenosis=intima
area/IEL areax100.
Time Course of Intimal Hyperplasia
To evaluate the time course of intimal hyperplasia, 2 animals
were killed immediately after the procedure and at 6, 24, and 48 hours
and 1, 2, and 4 weeks after balloon injury. Measurements of iliac
arteries were performed as described above.
Selectin Expression
To evaluate the time course of E-selectin expression on the
endothelium, 2 animals were killed at each of seven
predetermined time points: immediately after the procedure and at 6,
24, and 48 hours and 1, 2, and 4 weeks after balloon injury.
Immunohistochemical analysis was performed by previously
described methods16 on frozen sections prepared
as described above. Briefly, a Vectastain Elite ABC kit (Vector
Laboratories, Inc) was used with the mouse anti-rabbit E-selectin
monoclonal antibody 14G2 (5 µg/mL; Hoffmann-LaRoche). Negative
controls were obtained for all staining runs by use of an isotype
control antibody as the primary antibody. In addition, staining for
endothelial cells was performed with the
endothelial cell–specific monoclonal antibody
QB-END/40 (1:5 dilution, Accurate Chemical and Scientific Corp).
To evaluate the time course of L-selectin expression on circulating leukocytes after balloon injury, blood was drawn from 4 animals at predetermined time points: immediately after the procedure and at 6, 24, and 48 hours and 1 and 2 weeks after balloon injury. Flow cytometry was performed as previously described.17 Whole blood was prepared with a whole-blood lysing kit (Coulter Corp). The anti–L-selectin monoclonal antibody DREG-200 (5 µg/mL, Boehringer Ingelheim) was used. Mouse IgG1 (Becton Dickinson) was used as a negative control, and a mouse monoclonal antibody specific for CD11b, clone 198 (Serotec USA), was used as a positive control. Samples were run on a Coulter EPICS Elite ESP Cell Sorting System (Coulter Corp). Results are expressed as a percentage of the baseline mean channel fluorescence.
Effects of Selectin Blockade
The effects of blocking selectins on balloon injury were
evaluated in 16 rabbits. Before balloon injury as described above, the
rabbits were placed in the supine position, and a midline abdominal
incision was made, exposing the peritoneal cavity. After the peritoneum
was opened, six implantable osmotic pumps (Alza Corp) were placed in
the peritoneal cavity, and the cavity and skin were closed according to
standard surgical procedure. Each pump delivered a volume of 10 µL/h.
Eight animals received CY-1503 as a 10-mg/kg IV bolus followed
by 2 mg · kg-1 ·
h-1 IP (60 µL/h) for 1 week, and the other 8
animals served as the control group, receiving an equal volume (bolus
and infusion) of normal saline. Immediately after this, balloon injury
of the iliac artery was performed as previously described. There was
one intraprocedural death in the study group, leaving 7 animals in the
study group and 8 in the control group. Animals were killed at 4 weeks
as previously described, and measurements were made of vascular
rings.
In addition, sections were stained with hematoxylin-eosin and with Giemsa stain for further analysis by a pathologist blinded to specimen group. This analysis included assessment of plaque composition and inflammatory cell infiltration, which was graded subjectively as none, mild, or moderate.
Statistics
All data are expressed as the mean±SEM. Statistical
analysis was performed by ANOVA or Mann-Whitney statistics.
Values of P<.05 were considered statistically
significant.
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Results |
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Time Course of Intimal Hyperplasia
As shown in Fig 1
, our model
resulted in consistent intimal hyperplasia. Intimal growth was
first observed at 1 week after balloon injury and continued for the
entire 4-week study period.
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Selectin Expression
Fig 2 depicts photomicrographs of
arteries harvested at various time points after balloon injury that
were stained with an antibody to E-selectin. It can be seen that
E-selectin expression is first noted at 6 hours and appears to peak at
24 to 48 hours after balloon injury, with a return to baseline by 1
week. At the earlier time points, the E-selectin staining was patchy,
corresponding to regions of retained endothelium,
suggesting that the injury used in this protocol did not result in
complete deendothelialization (Fig 3).
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The time course of L-selectin expression on circulating leukocytes is
illustrated in Fig 4. A significant
increase was noted at 48 hours after injury, with values returning to
baseline by 1 week.
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Effects of Selectin Blockade on Intimal Hyperplasia
There was no difference in weight between the two experimental
groups (CY-1503 group, 3.0±0.1 kg versus placebo group, 3.0±0.1 kg).
At 4 weeks after injury, there was no difference between the two groups
in area within the external elastic lamina (91.7±4.7 versus
90.2±5.6 mm2) or in the media area
(24.9±0.9 versus 26.3±1.7 mm2).
The animals receiving CY-1503 exhibited significantly less intimal
hyperplasia, as determined by intimal area or intima-to-media ratio
(Fig 5). In addition, the lumen area was
significantly larger and the percent area stenosis was
significantly less in the CY-1503 group than in the saline group (Fig 5). There was no significant intimal hyperplasia in the contralateral
(noninjured) iliac arteries in either group. Fig 6 demonstrates
representative iliac arteries from each group as well
as a noninjured contralateral artery.
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Although there was less plaque in the treated group, both groups had similar plaque composition, consisting of myofibroblasts within matrix. The treated group had less inflammatory cell infiltration, with no or only mild amounts of lymphocytes and granulocytes visible, compared with mild to moderate amounts noted in the control group.
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Discussion |
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Our study demonstrates that expression of the CAMs E-selectin and L-selectin increases after balloon injury of rabbit iliac arteries. To the best of our knowledge, this is the first report of selectin expression after balloon injury in an animal model. In addition, blocking the selectins significantly attenuates the intimal hyperplasia that follows balloon injury. No previous study has attempted to limit selectin-mediated cell adhesion after balloon-induced vascular injury. These findings may have relevance to restenosis after balloon angioplasty in humans.
CAMs and Response to Injury
CAMs are glycoproteins found on formed elements in the
blood and on the surface of endothelial cells that
facilitate the adhesion of platelets and leukocytes to the vascular
endothelium during inflammation and in response to
vascular injury.8–11 Three major families of
CAMs are involved in this process: (1) selectins, (2) integrins, and
(3) the immunoglobulin superfamily. The adhesion cascade involves three
phases: (1) neutrophil rolling, (2) firm adhesion of neutrophils, and
(3) transmigration of cells across the vascular
endothelium.
The initial phase, neutrophil rolling, is mediated by interaction
of selectins with numerous ligands, the most important being the
carbohydrate
sialyl-LewisX.18 L-selectin
is constitutively expressed on leukocytes and is rapidly shed once the
cells become activated. E-selectin is expressed on
endothelial cells and slowly becomes activated
over 4 to 6 hours and then is only moderately activated.
P-selectin does not depend on new protein synthesis but rather is
stored in 
-granules of platelets and Weibel-Palade bodies of
endothelial cells.19,20 On
activation, these molecules are rapidly translocated to the cell
surface, where they are a part of the initial adhesion molecules
influencing leukocytes in the early inflammatory response.
Although De Servi et al21 demonstrated an increase in serum elastase levels after PTCA as evidence for granulocyte activation, only two previous studies have examined selectin expression after PTCA. Kurz et al22 evaluated serum levels of several inflammatory markers in patients undergoing elective PTCA. They demonstrated that after angioplasty, soluble E-selectin and soluble L-selectin are increased, with peak levels seen at 24 and 48 hours, respectively. The exact significance of soluble CAMs, which may be shed or may represent alternatively spliced forms, is still unclear. In another study, levels of L-selectin on leukocytes decreased immediately after PTCA, supporting the conclusion that shedding of L-selectin had occurred.23 In our model, L-selectin levels on leukocytes increased at 48 hours after balloon injury. This suggests that after PTCA, there may be an immediate shedding of L-selectin already on the leukocyte surface followed by a delayed increase in surface expression.
We were somewhat surprised to see expression of E-selectin very early after balloon injury, because this is expressed on endothelial cells, and we expected endothelial denudation from the balloon. However, the staining for endothelium did demonstrate the persistence of small foci of endothelium in this model.
In a recent study in human coronary atherectomy tissue, we found no difference in P-selectin or E-selectin expression in primary versus restenotic lesions.16 P-selectin but not E-selectin expression was increased in patients with unstable angina. The pathophysiology of unstable angina, involving plaque rupture, is very similar to that of the early period after PTCA, with inflammation probably playing a role in the early stages of both processes.24,25 It is possible that P-selectin may have been expressed early but returned to normal by the time of repeat intervention in patients with restenosis.
Other CAMs that play a role later in the cell adhesion cascade have also been studied. In a balloon endothelial denudation model of injury in normal rabbit aorta, Tanaka et al26 found an increase in expression of vascular cell adhesion molecule-1 in the regenerating endothelium as well as increased expression of intercellular cell adhesion molecule-1 (ICAM-1) on the endothelial and smooth muscle cells of the neointima. These CAMs mediate the firm adhesion stage, which follows neutrophil rolling. In another study, there was no change in the expression of soluble ICAM-1 up to 72 hours after PTCA.22
CAMs and Restenosis
The pathophysiology of coronary artery restenosis
appears to involve elastic recoil, thrombus formation, and intimal
hyperplasia with fibrocellular proliferation.2
Libby et al27 proposed a "cascade mechanism"
to explain restenosis pathobiology in which local thrombus,
blood coagulation, or mechanical injury activates
cytokine gene expression by macrophages and/or smooth
muscle cells within the plaque. This would evoke secondary,
self-sustaining, autocrine and paracrine growth factor and
cytokine expression by cells within the lesion, including
leukocytes. This could account for the observed lag between injury and
restenosis.
The multiplicity and redundancy of cytokine and growth factor pathways may explain why treatments targeted at any one growth factor may be unsuccessful. Accordingly, some investigators have sought to block a final common pathway by using antisense technology28 or monoclonal antibodies29 to interfere with cell division. Our group chose an alternative approach by examining the most likely initial steps involving selectin-mediated cell adhesion at the site of injury.
Before our study, there have been no data regarding the effects on restenosis of blocking selectin-mediated cell adhesion. Several studies have shown an association between increased expression of CAMs and restenosis. In preliminary studies with coronary sinus blood obtained after PTCA, Inoue et al31 found that restenosis correlated with increased platelet expression of P-selectin and leukocyte expression of sialyl-LewisX,30 but with decreased leukocyte expression of L-selectin. In addition, expression of the leukocyte integrin CD11b/CD18, which binds to ICAM-1 during firm adhesion, was also increased in patients with subsequent restenosis. In another small study, increased expression of CD11b and increased platelet adherence to leukocytes were noted in patients who later had restenosis.32
In the present study, selectin-mediated adhesion was blocked with CY-1503, a carbohydrate analogue of sialyl-LewisX that has been shown to protect against myocardial ischemia-reperfusion injury.13,14 In these previous studies, myeloperoxidase activity in the infarct region was shown to be decreased by CY-1503, consistent with decreased neutrophil infiltration. On the basis of determination of the duration of selectin expression after balloon injury, 7 days of drug treatment was used in the present study. Because of its short half-life, continuous infusion of the agent was necessary. The treated animals were similar in size to the control animals, suggesting that a similar amount of injury was produced in the two groups. In our study, CY-1503 resulted in a significant reduction in intimal hyperplasia. This was associated with observation of fewer inflammatory cells at 30 days. We did not necessarily expect a difference in inflammatory cells at 30 days, because selectin inhibition was used for only 7 days, and acute inflammation would be expected to be somewhat resolved by 30 days. Other investigators have also demonstrated inflammation after balloon injury in the rabbit model, which peaked at day 5 to 10.26
Previous studies have suggested that both intimal hyperplasia and vascular remodeling are important in the rabbit model of balloon angioplasty.33,34 In this study, there were no differences between the two groups in the area within the external elastic lamina, area within the internal elastic lamina, or the area of the media, suggesting that the beneficial effects were due to decreased intimal hyperplasia alone and that vascular remodeling probably played no greater a role in one group than the other.
Limitations
There are several potential limitations to this study. First, many
agents that are successful in animal models have not been effective in
reducing human restenosis.35 The rabbit
model used has some inherent problems, including balloon injury of
normal artery and a difference in the consistency and
composition of the subsequent atherosclerotic plaque in comparison with
human arteries. However, the animals are readily available,
inexpensive, and easily handled, and the iliac artery approximates the
size of the human coronary artery. Another potential limitation
is the relatively small sample size; however, the differences seen were
statistically significant. This study does not fully delineate the
exact mechanism by which the final results were achieved. We
hypothesize that the results are due to blockade of selectin-mediated
cell adhesion, because that is the known action of CY-1503; our
previous study of ischemia-reperfusion injury showed decreased
neutrophil activity, which correlated with decreased injury; and less
inflammation was noted in the treated group in this study. Because
CY-1503 blocks all selectin-mediated adhesion, we were not able to
specifically delineate the importance of each selectin individually. In
particular, because of the lack of a P-selectin antibody to rabbit
tissue, we were unable to examine the role of P-selectin in our model.
Finally, it is possible that we may have only delayed the development
of intimal hyperplasia in the treated animals.
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Acknowledgments |
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Dr Barron is the recipient of the J. Walter Libby Fellowship of the American Heart Association, Louisiana Affiliate. The authors thank David J. Lefer, PhD, for his technical advice, Barry A. Wolitsky, PhD, Hoffman-LaRoche, for the anti E-selectin antibody 14G2, Takashi K. Kishimoto, PhD, Boehringer Ingelheim, for the anti L-selectin antibody DREG-200, and William Robichaux, MD, for assistance with pathological analysis. We thank Clarence Noel, Steven Blesse, and Mickey Flynn for their technical assistance.
Received May 30, 1997; revision received July 11, 1997; accepted August 1, 1997.
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 J. Ludemann, K.-L. Schulte, O. Hader, S. Brehme, H.-D. Volk, and W.-D. Docke Leukocyte/Endothelium Activation and Interactions During Femoral Percutaneous Transluminal Angioplasty Vascular and Endovascular Surgery, July 1, 2001; 35(4): 293 - 301. [Abstract] [PDF]
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J. A. McPherson, K. G. Barringhaus, G. G. Bishop, J. M. Sanders, J. M. Rieger, S. E. Hesselbacher, L. W. Gimple, E. R. Powers, T. Macdonald, G. Sullivan, et al. Adenosine A2A Receptor Stimulation Reduces Inflammation and Neointimal Growth in a Murine Carotid Ligation Model Arterioscler Thromb Vasc Biol, May 1, 2001; 21(5): 791 - 796. [Abstract] [Full Text] [PDF]
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A. M. Miller, A. R. McPhaden, R. M. Wadsworth, and C. L. Wainwright Inhibition by leukocyte depletion of neointima formation after balloon angioplasty in a rabbit model of restenosis Cardiovasc Res, March 1, 2001; 49(4): 838 - 850. [Abstract] [Full Text] [PDF]
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J.-G. Bienvenu, J.-F. Tanguay, J.-F. Theoret, A. Kumar, R. G. Schaub, and Y. Merhi Recombinant Soluble P-Selectin Glycoprotein Ligand-1-Ig Reduces Restenosis Through Inhibition of Platelet-Neutrophil Adhesion After Double Angioplasty in Swine Circulation, February 27, 2001; 103(8): 1128 - 1134. [Abstract] [Full Text] [PDF]
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F. G. P. Welt, E. R. Edelman, D. I. Simon, and C. Rogers Neutrophil, Not Macrophage, Infiltration Precedes Neointimal Thickening in Balloon-Injured Arteries Arterioscler Thromb Vasc Biol, December 1, 2000; 20(12): 2553 - 2558. [Abstract] [Full Text] [PDF]
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S.-i. Hayashi, N. Watanabe, K. Nakazawa, J. Suzuki, K. Tsushima, T. Tamatani, S. Sakamoto, and M. Isobe Roles of P-Selectin in Inflammation, Neointimal Formation, and Vascular Remodeling in Balloon-Injured Rat Carotid Arteries Circulation, October 3, 2000; 102(14): 1710 - 1717. [Abstract] [Full Text] [PDF]
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Y. Merhi, P. Provost, P. Chauvet, J.-F. Theoret, M. L. Phillips, and J.-G. Latour Selectin Blockade Reduces Neutrophil Interaction With Platelets at the Site of Deep Arterial Injury by Angioplasty in Pigs Arterioscler Thromb Vasc Biol, February 1, 1999; 19(2): 372 - 377. [Abstract] [Full Text] [PDF]
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M. Roque, W. J.H. Kim, M. Gazdoin, A. Malik, E. D. Reis, J. T. Fallon, J. J. Badimon, I. F. Charo, and M. B. Taubman CCR2 Deficiency Decreases Intimal Hyperplasia After Arterial Injury Arterioscler Thromb Vasc Biol, April 1, 2002; 22(4): 554 - 559. [Abstract] [Full Text] [PDF]
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