© 1997 American Heart Association, Inc.
Articles |
Possible Mechanisms of Collar-Induced Intimal Thickening
From the Division of Pharmacology, University of Antwerp (UIA), B-2610 Wilrijk, Belgium (G.R.Y.D.M., D.J.M.V.P., H.B., N.B., A.G.H.), the Division of Vascular Surgery, University Hospital Antwerp (UZA), B-2650 Edegem, Belgium (P.V.S., R.B., R.V.), and the Division of Pathology, General Hospital Middelheim, B-2020 Antwerp, Belgium (M.M.K.).
Correspondence to G.R.Y. De Meyer, University of Antwerp (UIA), Division of Pharmacology, Universiteitsplein 1, B-2610 Wilrijk, Belgium. Email gdemeyer{at}uia.ua.ac.be
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Abstract |
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Abstract The positioning of a soft silicone collar around the rabbit carotid artery induces intimal thickening. We investigated to which extent occlusion of the vasa vasorum, damage of the perivascular nerve network, and/or changes in blood flow velocity contribute to intimal thickening. To this end, collars with different bores (diameter of inlet and outlet) were positioned around the carotid artery of male rabbits for 14 days. In another experiment, 75% of the wall of fitting collars was removed (open collar). In the midcollar region, the cross-sectional area of the intima reached a maximum (72±14 mm2/1000) when the endings of the collar fitted the artery closely. Removal of the side wall of these fitting collars reduced intimal thickening by 90%. Examination of unoperated carotid arteries never showed penetration of the adventitia or the media by vasa vasorum. The perivascular neuronal network in the region surrounded by a closed or an open collar was almost completely lost as compared with the zones outside the collar. Both the closed and open collar slightly bent the artery and increased the peak systolic velocity, measured with pulsed color Doppler after 6 hours, to a similar extent as compared with the proximal zone outside the collar. After 2 weeks, the peak systolic velocity within both the closed and open collar was partly normalized and was statistically not different from the proximal zone outside the collar. In conclusion, the geometry of the collar influenced the extent of intimal thickening, whereby more intimal thickening was obtained with a collar whose endings fit the carotid artery, rather than with a loose collar. Moreover, a closed structure was essential. The results obtained with the open collar exclude occlusion of vasa vasorum, damage of the perivascular neuronal network, kinking of the artery, and changes in blood flow velocity as major factors in the collar-induced intimal thickening. Our findings are consistent with the possibility that intimal thickening is the consequence of the combination of both vascular injury and hindrance of transmural flow by the collar. The obstruction of transmural fluid transport may then lead to retention of toxic metabolites, and/or cytokines within the segment enclosed by the collar.
Key Words: atherosclerosis • smooth muscle cells • flow cuff • intima
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Introduction |
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The positioning of a soft silicone collar around the carotid artery of rabbits induces intimal thickening,1 2 3 4 5 6 7 8 9 10 which is considered as a site of predilection for atherosclerosis.11 One great advantage of this model is that these changes occur rapidly (within 14 days) and that normal and intima-bearing vessels can be obtained from the same animal. Furthermore, the collar-induced intimal thickening occurs with minimal medial smooth muscle cell damage5 under an uninterrupted endothelial cell layer.6
However, the mechanism of intimal thickening in this model is not clear. Several factors have been suggested: response to inflammation,12 hypoxia resulting from obstruction of the vasa vasorum feeding the media,1 loss of the perivascular innervation,13 and changes in blood flow velocity due to kinking of the carotid artery and associated vasoconstriction, even though the silicone collar is nonocclusive.14 Moreover, in the literature there is no uniformity in the dimensions of the collar (eg, bore of the endings). This may possibly explain the differences in the extent of intimal thickening among research groups. The aim of the present study was to investigate whether hypoxia due to obstruction of the vasa vasorum, damage of the perivascular neuronal network, and/or hemodynamic changes (blood flow velocity) contribute to the intimal thickening.
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Methods |
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Collar Types and Surgery
Male New Zealand white rabbits were anesthetized with sodium pentobarbital (30 mg/kg IV), and both carotid arteries were exposed surgically. The collars were longitudinally split silicone collars of different geometry (types 1A, 1B, 1C, 2) were used (Table 1
, Fig 1).
Two collars per animal were implanted (one around the left and one
around the right carotid artery). In another series of experiments, the
side wall of collar type 2 was removed by 75%, leaving two strips (one
on top, one on the bottom) connecting the edges of the collar (open
collar). The open collar was positioned around the left and right
carotid artery, at random. The contralateral artery was surrounded by a
closed collar. The part of the carotid artery proximal and distal
outside the collared region was sham operated, ie, separated from the
surrounding connective tissue and the vagus nerve, receiving a similar
stretch. These regions served as internal control.
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The collars (both open and closed) were sealed with silicone (Silastic
732 RTV) as described earlier.2 3 4 5 6 For this purpose, a
minimal amount of glue was used. It is important that contact of glue
with the carotid artery is avoided since it causes a localized loss of
-smooth muscle cell actin in the outer media. After collar
implantation, the carotid arteries were returned to their original
position and the wounds were sutured. The rabbits were fed a standard
laboratory chow, and the collars were left in position for 14 days.
Histology
The rabbits were killed with sodium pentobarbital (60
mg/kg IV). Both the left and right carotid arteries were
dissected and rings (3 mm long) were cut from regions central
within the collar, and upstream (proximal sham) and downstream (distal
sham) outside the collar. The segments were immediately fixed in
methacarn fixative (methanol:1,1,1-trichloroethane:glacial acetic
acid, 60:30:10 by volume) or 4% neutral formalin. The tissues were
dehydrated simultaneously in a graded series of isopropanol
(70% to 100%) followed by toluol before embedding in paraffin.
Transverse sections were cut and stained with Sirius hematoxylin.
Immunohistochemical stainings were performed for -smooth muscle cell
actin (monoclonal anti--SMC actin antibody, dilution 1:2000,
Sigma, St Louis, MO) and for neuromodulin (monoclonal antibody NM4,
dilution 1:2000, gift of the Born Bunge Foundation, University of
Antwerp, Belgium15 ). For the detection of the antibody
against -SMC actin, the sections were incubated with rabbit
anti-mouse peroxidase for 45 minutes; the NM4 antibody was detected
using an anti-mouse ABC kit (Vector, Burlingame, Calif). The
specificity of the NM4 antibody was tested in different rabbit tissues
of which the staining patterns were known. For negative controls, the
primary antibody was omitted.
Vasa Vasorum
Cross-sections of methacarn-fixed carotid arteries (both
unoperated and collared with the different types of collars) were
immunostained for both CD31 (gift of Dr. R. Bicknell,
University of Oxford, UK) and vWf (Binding Site, Birmingham,
UK6 ) to detect endothelial cells in the
vasa vasorum. Vasa vasorum were defined as blood vessels originating
from the adjacent small arteries and that form a dense capillary
network in the adventitia.16 The adventitia was defined as
the dense collagenous layer surrounding the media of arteries and
veins.
Quantification of Intima and Neuromodulin
The cross-sectional area of intima and media was measured
with a digitizing tablet and the Sigma Scan software package (Jandel
Scientific, Erkrath, Germany). From each artery, one section of the
midcollar part, stained with Sirius hematoxylin, was used. Without
knowing from which treatment group the carotid segment originated, the
demarcations between the adventitia and media, the intima and media,
and the luminal circumference were traced. In this way, the areas
occupied by intima and media were established.
To quantify the area of material immunoreactive for neuromodulin, a color image analysis system was used (PC IMAGE COLOUR, Foster Findlay Associates Ltd, Newcastle-upon-Tyne, UK). All the nerve fibers at the interface of media and adventitia were included in the analysis. Nerves farther away from the media (in the periadventitia) were not taken in account because their presence depends on the amount of periadventitial tissue that is removed. There was no immunoreactivity in the media and intima. The antibody recognized neuromodulin, which is expressed in all nerve fibers. The results were obtained from the central part of the collared zone, where the collar does not touch the artery. The sham segments were taken from both the proximal and distal zones outside the collar.
Doppler
Carotid duplex ultrasonography under anesthesia
(sodium pentobarbital, 30 mg/kg IV) was performed along the
common carotid artery 6 hours and 14 days after placing type 2 collars
using a Toshiba SSH140 linear probe imaging at 7.5 MHz, and peak
systolic velocity was measured with pulsed color Doppler at
5 Hz and an angle of 60°.17 18 19 This angle could be
visualized and checked during the procedure. The rabbits were lying in
a prone position, but the head was kept upward to place the probe
against the neck. The carotid artery was visualized by ultrasonography.
Doppler analysis was performed approximately 1 cm upstream
from the collar and in the midregion within the collar. The region just
downstream from the collar was also used in some animals. The peak
systolic velocity was also determined in unoperated carotid
arteries (n=5).
Materials
Sodium pentobarbital was obtained from Psyphac, Brussels,
Belgium, and silicone (MDX4-4210, Dow Corning) and silicone glue
(Silastic 732 RTV) from the Compagnie Commerciale de Matières
Premières (CCMP), Antwerp, Belgium.
Data Analysis
All data are given as means±SEM. If the variances of the
samples were unequal, logarithmically transformed values were
analyzed. Comparison of the intimal area between the collar
types was done using analysis of variance followed by the
Student-Newman-Keuls test. The intimal area was compared between closed
and open collar using the Student's two-tailed paired t
test. The NM4 positive area was compared using analysis of
variance with collar (closed or open) and position (proximal outside
collar, distal outside collar, central in collar) as within subject
factors. Peak systolic velocity was compared using
analysis of variance with collar (closed or open) and position
(central in collar or upstream from collar) as within subject factors.
For the statistical analysis, the SPSS for Windows package
(SPSS, Chicago, Ill) was applied. A 5% level of significance was
selected.
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Results |
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Amount of Intimal Thickening
In the midcollar region, the area of the intima increased with a decreasing bore (Fig 2
). Regression
analysis of the data (x-axis: bore of the endings, y-axis:
intimal area) resulted in a linear relationship with a slope of -29±8
and y-intercept 113±19 (r=-0.43, n=59,
P<.001). Removal of the side wall of collar type 2
(fitting) significantly prevented intimal thickening (Fig 2). The value
of the open collar was not different from sham-operated segments.
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In another series of experiments, we could demonstrate that closed collars that had been sealed with two strings, without application of glue, induced intimal thickening similar to the collars sealed with the minimal amount of glue. Open collars sealed with two strings (no application of glue) did not induce intimal thickening, similar to the open collars sealed with glue (results not shown).
Perivascular Innervation
Both in the closed (all types, results only shown for type 2) and
open collar, the immunoreactivity for neuromodulin disappeared almost
completely as demonstrated by the NM4 antibody. In contrast, both the
distal and proximal regions outside the collar showed preserved
immunoreactivity (Fig 3, Table 2). The NM4 positive area in the proximal
region outside the collar did not differ from the distal region outside
the collar.
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Vasa Vasorum
Segments from unoperated carotid arteries and from carotid
arteries surrounded with the different collar types were
immunostained for vWf and CD31 to demonstrate
endothelial cells of microvessels. The intima of all
vessels examined was lined by a continuous layer of CD31-positive and
vWf-positive cells. Neither CD31 nor vWf immunopositive cells were
detected in the media or in the adventitia of any artery. We could
detect microvessels only in the fibroadipose tissue outside the
adventitia (Table 3). These microvessels
often surrounded nerves (vasa nervorum) or were thin-walled, pointing
to veins and lymph vessels.
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Blood Flow Velocity
The peak systolic velocity increased to a similar extent
in both the collared and open collared region of the carotid artery
after 6 hours as compared with the proximal zone outside the collar
(Fig 4). After 2 weeks, the mean peak
systolic velocity in both the closed and open collar was partly
normalized and was statistically not different from the proximal zone
outside the collar. There were no differences between the values of
closed and open collars after either 6 hours or 2 weeks. The peak
systolic velocity in the proximal zone outside the collar did
not differ from unoperated carotid arteries (data not shown). The peak
systolic velocity ratio (central zone within the
collar/proximal zone outside the collar) amounted to 1.60±0.20 for the
closed collar after 6 hours, 1.44±0.17 for the open collar after 6
hours, 1.33±0.18 for the closed collar after 2 weeks, and 1.28±0.25
for the open collar after 2 weeks (n=7).
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In the region just downstream from the collar (closed and open),
bending of the artery and turbulence were noticed (Fig 5). In this region, the peak
systolic velocity (m/s) amounted to 1.41±0.14 downstream from
the closed collar after 6 hours, 1.23±0.16 downstream from the open
collar after 6 hours (n=4), 1.29±0.17 downstream from the closed
collar after 2 weeks, and 0.91±0.26 downstream from the open collar
after 2 weeks (n=2). Some bending of the carotid artery was always seen
after collaring. The angle of the deviation of the normal path was
relatively small (approximately 30°), and there was apparently no
difference among the different collars.
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Discussion |
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Several explanations have been proposed to explain collar-induced intimal thickening: loss of perivascular innervation,13 occlusion of vasa vasorum,1 changes in blood flow velocity,14 kinking of the carotid artery, inducing turbulence or changes in flow direction.14 The present study focuses on these possibilities.
Perivascular Innervation
Scott et al13 demonstrated that in regions of the
carotid artery where intimal thickening occurred, the perivascular
innervation was lost. This was confirmed in the present experiment.
The authors postulated four possible explanations for the denervation:
direct mechanical pressure by the collar at the endings, localized
ischemia secondary to occlusion of vasa vasorum by the collar
endings, retention of potentially toxic metabolites in the collar, or a
combination of these possibilities. The results with the open collar,
in which the neuronal network was lost to the same extent, excluded
retention of potentially neurotopic metabolites as an explanation for
the loss of the perivascular neuronal network. Moreover, since the open
collar did not induce intimal thickening, it is clear that there is no
association between loss of the perivascular neuronal network and
collar-induced intimal thickening. Indeed, a correlation between NM4
and the intimal area was not present as NM4 positivity strongly
decreased or disappeared almost completely in all collars (all types,
both closed and open); however, intimal thickening was either prominent
(closed type 2 collar), very moderate (closed type 1A collar), or
absent (open type 2 collar).
Occlusion of Vasa Vasorum
The geometry of the collar significantly influences the extent of
intimal thickening, whereby the bore of the endings is an important
parameter. More intimal thickening is obtained with a
collar whose endings fit the carotid artery, rather than with a loose
collar. Type 2 collars were used to make possible a comparison with the
results of Soma et al.7 8 There was no significant
difference in intimal thickening induced by collar type 1C and type 2,
confirming that the bore of the endings of the collar (1.8 mm in
both cases) is an important parameter. This finding appears
to be in keeping with the hypothesis that collar-induced intimal
thickening can be explained by medial hypoxia secondary to
occlusion of the adventitial vasa vasorum by the endings of the
collar.1 However, the results obtained with the open
collar demonstrated that this hypothesis must be dismissed, since the
endings of the open collar also fit the carotid artery without leading
to intimal thickening. Moreover, examination of unoperated carotid
arteries never showed penetration of the adventitia or the media by
microvessels. We could detect microvessels only in the fibroadipose
tissue outside the adventitia. These microvessels often surrounded
nerves (vasa nervorum) or were thin-walled, pointing to veins and lymph
vessels. These results agree with those of Wolinsky and
Glagov,20 who described that vasa vasorum penetrate the
media when the arteries contain 29 or more smooth muscle cell layers.
The media of the rabbit carotid artery consists of only 10 to 12
layers. In veins, however, vasa vasorum are in general more abundant in
the media and adventitia and may even penetrate up to the
intima.16
In a study in saphenous vein grafts,21 we found after a coronary bypass operation a pronounced medial smooth muscle cell loss and necrosis, which could be linked to an interruption of vasa vasorum. Indeed, hypoxia may lead to necrosis 15 days after vasa vasorum removal in the canine aorta22 or apoptosis in cardiomyocytes.23 24 In contrast, in the rabbit carotid artery 14 days after collaring there is no manifest medial necrosis or apoptosis (results not shown). Moreover, after the positioning of an open collar, vasa vasorum would also be interrupted, although this collar did not induce intimal thickening. Similarly, removal of the vasa vasorum of the canine-aorta22 did not lead to intimal thickening after 15 days. Furthermore, the thyroid artery, a small branch of the carotid artery, was occasionally enclosed by the collar. Although its media contains only four smooth muscle cell layers, it developed a very striking intimal thickening (intima/media ratio>1.5) after 14 days, as shown previously.5 Arteries of this caliber (diameter 350 µm or less) do not contain vasa vasorum to provide nutrition to the medial smooth muscle cells.16 Therefore, hypoxia of the media due to occlusion of the vasa vasorum cannot explain collar-induced intimal thickening in these small arteries.
Taken together, these data provide evidence that interruption of vasa vasorum cannot explain intimal thickening after collaring. The possibility that the collar interferes with the exchange of fluids and nutrients between the artery and the surrounding tissue remains open (see below).
Blood Flow Velocity
Local disturbances in blood flow have been proposed as an
explanation for the focal nature of atherosclerosis.
Both the high25 26 and low shear27 28 29 30 areas
have been considered as primary sites of atheroma
formation. Also in the collar model, blood flow velocity changes along
the carotid artery have been proposed as an explanation for intimal
thickening.14 31 The increased velocity ratio observed 6
hours after collaring (1.60±0.20) was in perfect agreement with the
data of Yong et al14 one day after collaring (1.69±0.13).
The collar did not induce a hemodynamically significant
stenosis; the peak systolic velocity corresponded to a
stenosis of approximately 50%. Since peak systolic
velocity increased to the same extent in arteries surrounded by open
collars, which did not develop intimal thickening,
hemodynamic changes such as increased shear appear not
to be involved in the induction of intimal thickening. Thubrikar and
Robicsek32 suggested that pressure-induced wall stress
rather than increased or decreased shear is the principal factor in the
localization of intimal thickening.
Kinking of the Carotid Artery
Carpenter et al33 reported that collar implantation
in general does not occlude the carotid artery and causes only a slight
and gradual degree of curvature to the vessel as demonstrated by
magnetic resonance imaging. This was confirmed in the present
study. The bending is the consequence of the space of the collar that
opposes the smooth normal repositioning of the carotid artery between
the muscle layers at the distal end of the collar. Both the closed and
open fitting collar slightly bent the artery and produced turbulence
just downstream from the collar. Peak systolic velocity in this
region did not differ between closed and open collared arteries. Since
only the closed collar induced intimal thickening, kinking of the
carotid artery, as suggested by Yong et al,14 and
disturbances of the laminar flow appear to be unlikely as
explanations for the intimal thickening.
Since the results obtained with the open collar exclude occlusion of vasa vasorum, inhibition of neuronal activity, kinking of the artery, and changes in blood flow as major factors in the collar-induced intimal thickening, alternative mechanisms must be involved. Injury of the media and obstruction of transmural flow by the collar represent other possible explanations.
Injury of the Media
In a review on neointima formation and intimal
thickening, Jackson34 pointed out that injury of the
smooth muscle cells is a consistent feature. The injury may
escape detection by light microscopy but is illustrated by the abrupt
and dramatic increase of smooth muscle cell proliferation, the first
prerequisite for intimal thickening. Several lines of evidence indicate
that placement of the collar causes injury of the media as well. First,
we have shown immunohistochemically that even a sham operation induces
a 10-fold increase of the proliferation rate of the medial smooth
muscle cells.5 Moreover, the sham-operated arteries
demonstrate focal areas of endothelial denudation, an
increased rate of endothelial cell replication, and
local adhesion but no infiltration of leukocytes.6 These
findings illustrate unequivocally that perivascular manipulation of the
artery, even without placing a collar, evokes vascular injury, which
extends across the media to the intima. Yet, since intimal thickening
does not occur in sham-operated arteries, the medial injury and the
transient, focal loss of endothelial
cells6 appear to be insufficient to evoke the subsequent
step in the three-wave paradigm of intimal thickening, smooth muscle
cell migration.34 The present data indicate that
smooth muscle cell migration takes place only if the artery is fitted
within a closed collar. This may be due to aggravation of the
operation-related injury by the collar. This idea is supported by the
observation that the collar, but not the sham operation, elicits
infiltration of neutrophils into the media,5 a hallmark of
acute injury of tissues. However, our preliminary data suggest that
smooth muscle cells do not migrate into the intima as a result of the
neutrophil influx,35 which confirms findings in a model in
which intimal thickening is evoked by electrical
stimulation.36 37
Obstruction of Transmural Flow
In accordance with the focal loss of endothelial
cells, which occurs in sham-operated arteries as well,6
and an increased endothelial permeability associated
with the transendothelial migration of
neutrophils,5 there is a dramatic, 40- to 50-fold increase
in transarterial fibrinogen flux and accumulation of
fibrinogen in the artery wall 1 day after collar placement as compared
with the unoperated contralateral artery.38 Furthermore, 6
hours after collar placement, the media already shows clear, focal
immunoreactivity for fibrinogen, which has disappeared 2 weeks
later.39 These data demonstrate unequivocally that the
collar increases the transmural flow and leads to retention of
plasma-derived macromolecules in the vessel wall in the early period
after its placement. The formation of fibrin degradation products
may even contribute to intimal thickening since they are potent
mitogens.38 40
The finding that the open collar did not induce intimal thickening is in agreement with the assumption that obstruction of transmural flow is necessary for the intimal hyperplasia. Moreover, Lange41 described induction of intimal thickening by surrounding blood vessels with wax. Also in this system, prevention of the removal of toxic factors, growth factors/cytokines in combination with the mechanical injury of the vessel wall, may have contributed to intimal thickening. Occlusion of lymph vessels could contribute to the retention of substances after surrounding a closed collar around the carotid artery.42 However, although lymphatic drainage may be obstructed, there was no overt edema after application of a soft silicone collar.
In conclusion, the combined data suggest that intimal thickening is presumably the consequence of the combination of both vascular injury and hindrance of transmural flow by the collar. The obstruction of transmural fluid transport may then lead to retention of toxic metabolites and/or cytokines within the segment enclosed by the collar.
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Acknowledgments |
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This work was supported by grant No. 3.0009.93 of the Fund for Medical Scientific Research (Belgium) and the Belgian Programme on Interuniversity Poles of Attraction (Convention 25), Prime Minister's Office, Science Policy Programming. Dr. De Meyer is Research Associate, and Dr. Van Put is Research Assistant of the Fund for Scientific Research (FWO), Flanders. We thank François Jordaens, Rita Van Den Bossche, Anne-Elise Van Hoydonck, and Ludo Zonnekeyn for technical assistance and Liliane Van den Eynde for typing the manuscript. We acknowledge the Born Bunge Foundation (University of Antwerp, Belgium) for the gift of antibody NM4. We also thank Dr. Maurizio Soma (Institute of Pharmacological Sciences, University of Milan, Italy) for the gift of type 2 collars and Dr. R. Bicknell (University of Oxford, UK) for the gift of the CD31 antibody. The results have been presented in part at the Winter Meeting of the British Pharmacological Society in Brighton, December 1994.
Received November 27, 1995; accepted December 12, 1996.
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