© 1997 American Heart Association, Inc.
Articles |
Redistribution of von Willebrand Factor in Porcine Carotid Arteries After Balloon Angioplasty
From the Cardiovascular Sciences Research Group, Departments of Haematology (J.C.G., H.R.) and Cardiology, Pharmacology, Therapeutics and Toxicology (A.P.B., J.M.L.), University of Wales College of Medicine, Cardiff, United Kingdom.
Correspondence to Dr. J.C. Giddings, Haematology Department, University of Wales College of Medicine, Heath Park, Cardiff, CF4 4XN, UK. E mail Giddings{at} Cardiff.ac.uk
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Abstract von Willebrand factor (VWF) is a well-characterized multimeric glycoprotein present in platelets and plasma and synthesized by vascular endothelial cells and megakaryocytes. Its role in platelet-vessel wall interactions has been studied extensively, but its involvement in intravascular events after balloon angioplasty has not been clarified. VWF antigen is not present in porcine arterial endothelium (except for the pulmonary artery) but is readily detected in porcine venous endothelial cells. We have examined the localization of VWF in porcine vessel walls during neointima formation after bilateral carotid balloon-angioplasty. Endothelium was denuded by balloon injury but regenerated by 7 days and was fully confluent by 42 days. VWF was detected at the site of injury in localized, adherent platelet aggregates at 10 minutes after angioplasty that were not present at later time points. A well-demarcated homogeneous layer of VWF was observed on the luminal surface from 30 minutes to day 7, but there was a progressive shift of positive staining from the lumen to the outer media from days 1 to 7. VWF was also strongly detected at sites proximal and distal to the balloon injury from 30 minutes to day 7, although endothelial disruption was minimal and the monolayer remained substantially intact at these sites. Regrowing endothelial cells appeared to contain granular VWF from days 12 to 21, but this was not readily evident at later time points. The results suggest that balloon injury is associated with deposition and medial absorption of plasma or platelet VWF in this porcine model over a time period that precedes and overlaps vascular smooth muscle proliferation and endothelial recoverage. The findings provide evidence to support the concept of a wider role for VWF in tissue injury responses.
Key Words: von Willebrand factor • angioplasty • porcine carotid arteries
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Introduction |
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Balloon angioplasty inevitably leads to endothelial denudation and exposure of thrombogenic matrices. The loss of vascular integrity acts as a potent stimulus to coagulation, and thrombin generation enhances platelet activation and aggregation on subendothelial connective tissues. Fresh platelet thrombus is usually found therefore at sites of angioplastic injury.1 2 3 4 Moreover, adhesion of platelets to the exposed subendothelium is believed to be the first event in the thrombotic process, and the extent of acute platelet deposition may be an important feature in determining the outcome of angioplasty. Platelet adhesion is followed by degranulation with the local release of substances that cause vasoconstriction and encourage additional hemostatic responses.5 The process involves interaction of platelet membrane glycoproteins including GP Ib and GP IIb/IIIa with subendothelial collagen and plasma proteins, especially VWF.6 Furthermore, the release of agonists, including platelet-derived growth factors, which promote smooth muscle cell proliferation and migration, has been implicated in the pathogenesis of intimal hyperplasia, which underlies the development of restenosis and atherosclerosis after angioplasty.7 8 9
von Willebrand factor (VWF) is a well-characterized macromolecular glycoprotein synthesized by vascular endothelial cells and megakaryocytes and present in plasma, platelets, endothelium, and subendothelium.10 11 Its role in platelet-vessel wall interactions has been extensively studied, and its prohemostatic properties have been clearly defined.6 Despite the significant progress in elucidating the nature of VWF, however, many aspects of the biology of VWF are not fully understood. In the present context, it may be especially pertinent that the origin of VWF in the subendothelial matrix has been questioned. For example, Sussman and Rand12 reported that extracellular deposition of VWF in rabbit aortas required the presence of viable endothelial cells and that relatively trivial amounts of plasma-derived VWF were present in neointimal connective tissue after balloon catheter deendothelialization. In contrast, Reidy et al13 identified increased endothelial VWF and its localization in the matrix of denuded rat arteries 2 weeks after balloon catheter angioplasty. Furthermore, Kockx et al14 demonstrated that VWF was progressively deposited in extracellular spaces during cuff-induced neointima formation in rabbit carotid arteries. The reasons for these apparent discrepancies do not appear to have been fully resolved.
In addition, recent molecular genetic studies have identified conserved structural homologies in VWF and other adhesive proteins involved in cell-cell interactions15 16 17 18 19 and in gastrointestinal mucins.20 21 22 These findings provide intriguing evidence to suggest that the role of VWF extends beyond that involved in primary hemostatic mechanisms, and it has been postulated that VWF might contribute to diverse adhesive responses such as those involved in erythrocyte binding to microvascular endothelium,23 tumor cell adhesion, migration, and dissemination.24 25 26 VWF is not present in significant amounts in porcine arterial endothelium (except for pulmonary artery) but is readily detected in porcine venous endothelial cells.27 28 29 30 Moreover, this heterogeneity is observed at the level of VWF mRNA, and the marked variation in cellular localization offers an especially useful means to study the control of VWF-related mechanisms in vivo.31 We have adopted a porcine model, therefore, to examine the distribution of VWF in subendothelial matrices in this species and to investigate the potential role of VWF in neointima formation after balloon angioplasty.
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Methods |
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Porcine Model
Large white pigs aged 3 to 4 months with a mean weight of 33.8 kg were sedated with ketamine (750 mg IM), and anesthesia was induced by inhalation of 0.5% halothane and maintained by the continuous infusion of fentanyl (0.01 mg/mL), etomidate (0.04 mg/mL), and ketamine (1 mg/mL) into the marginal ear vein. The animals were mechanically ventilated, and continuous ECG monitoring was performed throughout the procedure. After surgical exposure, a 9F sheath was inserted into the right femoral artery, and arterial blood was monitored thereafter through its sidearm. All experiments were conducted in accordance with British Home Office guidelines on animal experimentation.
Angioplasty
Angioplasty was performed using an 8F 8-mm Meditech
balloon catheter. The balloon to artery ratio was 1.5-2 to 1. The
catheter was advanced under fluoroscopic control into the left carotid
artery and positioned at a level between cervical vertebrae 1 and 3.
The balloon was inflated at 6 atmospheres for a duration of 30 seconds
on five separate occasions with an interval of 60 seconds between each
inflation. At the end of the fifth inflation, the balloon catheter was
pulled back into the common carotid artery and then advanced without
delay into the right carotid artery. The dilatation protocol was
repeated at a level in this artery similar to that in the left carotid
angioplasty. The total duration of the angioplasty procedure was 16 to
18 minutes in all experiments with the interval between left and right
carotid kept at 1 to 3 minutes. Animals (n=4 at each time point) were
sacrificed by administration of an overdose of pentobarbital at 10
minutes, 30 minutes, 1 day, 7 days, 12 days, 21 days, or 6 weeks after
angioplasty. After desanguination using physiologic saline
(Krebs-Ringer solution), blood vessels were carefully excised and
processed immediately without storage.
Isolation and Culture of Endothelial Cells
Endothelial cells were harvested from the
undamaged carotid artery and jugular vein of control animals by
intraluminal collagenase digestion and cultured in medium
199 supplemented with 10% fetal calf serum as previously
described.27 In outline, cells were obtained after 0.05%
collagenase incubation (Sigma type I) for 8 minutes at
37°C. Cells were seeded in six-well plastic culture dishes in an
humidified atmosphere of 5% CO2/95% air at approximately
2x105 cells per mL of medium. Penicillin, 200 units per
mL, and streptomycin, 200 µg per mL, were added as antibiotics;
amphotericin B, 5 µg per mL, as a fungicide; and the medium was
enriched with 2 mM glutamine and 20 µg per mL of
endothelial cell growth supplement. Except where
indicated, all tissue culture reagents were obtained from Gibco
Laboratories (UK).
Histological Analysis and
Morphometry
Segments of blood vessels were recovered from control animals
and from the site of balloon injury together with distal and proximal
portions. The arteries were cleaned and stripped of adventitia.
Localized arterial dilatation and vessel wall thickening
was apparent at the site of balloon injury. The segments were divided
into six equal samples approximately 0.5 cm long and were embedded
in paraffin for conventional staining or were snap-frozen at -160°C
for immunocytochemistry. Transverse histological
sections (4 µm) were taken from each segment and were examined
with hematoxylin-eosin and Van Giesen elastic stain. Sections were
coded for blinded analysis.
Morphometry was performed using a video microscope (Olympus) linked to an IBAS 2 image analyser (Kontron, FRG) incorporating a computer graphics program (Videoplan, Kontron) that allowed the manual selection and delineation of areas of interest. In sections without medial dissection, the intimal area was defined as the area separating the internal elastic lamina from the lumen, and the medial area as the area between the internal and external elastic laminae. The circumference of the internal elastic lamina was also measured. In the majority of sections, medial dissection had occurred, and the preexisting media was easily identified by the presence of organized elastic fibers. The neointimal cells overlying the remaining intact internal elastic lamina and those in the area of medial repair were smaller, more closely packed, and separated by diffuse elastin staining tissue. In such sections, the area of neointima and the area of medial repair were summed for quantitation of the response to injury.
VWF Staining
VWF was identified by indirect
immunofluorescence using a previously
characterized, specific polyclonal antibody to porcine VWF raised in
rabbits.27 The analyses were undertaken by three
independent observers, and endothelial staining
patterns were graded between absent (-) and strongly positive or
confluent (+++). Preliminary assessment using this semiquantitative
scale indicated that each observer identified the same pattern of
staining intensities and that the between-observer variation was
consistently within one grade. All photomicrographs of the
immunocytochemistry were obtained under identical conditions using a
Zeiss Standard RA microscope fitted with an epifluorescence
condenser.
DBA Lectin Staining
The lectin from Dolichos biflorous agglutinin (DBA)
(Sigma) was used to identify the endothelial
monolayer.32 Sections of carotid artery were rinsed in
water, and endogenous peroxidase activity was
inhibited by incubation at room temperature for 5 minutes in 3% (v/v)
hydrogen peroxide in distilled water. After rinsing, sections were
incubated with peroxidase labeled DBA lectin in phosphate-buffered
saline (pH 7.2) for 30 minutes at room temperature. Sections were then
rinsed and the color was developed using the diaminobenzidine-hydrogen
peroxide reaction. After washing, sections were lightly counterstained
with haematoxylin, dehydrated through alcohol, cleared in xylene, and
mounted. Positive cells were identified as those with blue nuclei and
brown cytoplasmic staining. Negative cells had blue nuclei and no
cytoplasmic staining.
Smooth Muscle Cell Staining
Vascular smooth muscle cells were identified using a :1:200
dilution of primary antibody to 
-smooth muscle actin (1A4, Sigma),
as described by Soyombo et al.33 Sections were then
incubated with a :1:400 dilution of biotin-conjugated goat antimouse
immunoglobulin IG (Sigma) followed by a :1:200 dilution of
Extr-Avidin horseradish peroxidase (Sigma). Color was developed as
described above, using diaminobenzidine-hydrogen peroxidase, and the
sections were lightly counterstained with hematoxylin.
Cell Proliferation
A relative measure of the number of active vascular smooth
muscle cells in the cell cycle was studied by expression of
proliferating cell nuclear antigen (PCNA). This is an essential DNA
polymerase delta accessory protein34 that is expressed
maximally during the S-phase of the cell cycle.34 35
Sections were incubated with a primary antibody to PCNA (PC10, DAKO
Ltd, UK) at a dilution of :1:100 for 1 hour and then with a
biotinylated antimouse immunoglobulin G secondary antibody (Vector
Laboratories, UK) at a dilution of :1:50 for 30 minutes. A solution
of avidin-biotin complex (DAKO) in TRIS-buffered saline was applied for
30 minutes, and color finally developed with diaminobenzidine-hydrogen
peroxide. Sections were then lightly counterstained with hematoxylin as
described above. Cell counting was performed at high magnification
using a video microscope linked to a computer program (Videoplan,
Kontron, FRG). The PCNA index36 was defined as the number
of PCNA-positive cells divided by the sum of PCNA-positive and
-negative cells and expressed as a percentage.
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A summary of the findings is given in Table 1
. As expected, VWF was not detected on
the luminal endothelium in histological
sections of porcine carotid artery although abundant quantities of this
protein were found in similar sections of porcine jugular vein (Fig 1, a and b). This marked contrast between
arterial and venous endothelium was
confirmed in sections of aorta where adventitial venules were strongly
positive for VWF alongside adjacent arterioles that were negative (Fig 1d). It is also noteworthy that VWF was located in the vasa vasorum of
the porcine carotid artery (Fig 1c), demonstrating that the staining
procedure was effective on this type of fresh-frozen tissue. The
presence of a luminal endothelial surface on the normal
carotid artery and identification of the vasa vasorum were confirmed by
conventional hematoxylin and eosin staining of serial sections (Fig 1, e and f). In addition, VWF could not be identified in cultured
endothelial cells from carotid artery (Fig 2a) whereas a positive reaction, typical
of the Weibel-Palade bodies characteristically found in human
endothelial cells, was observed in cultured cells from
porcine jugular vein (Fig 2b). The faint fluorescence seen in
the arterial cells was also observed in control cells
treated with nonimmune rabbit serum (Fig 2, c and d) and reflected a
low level of nonspecific autofuorescence.
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Ten minutes after balloon angioplasty, VWF was detected in
variably sized platelet aggregates, adhering to the injured carotid
site (Fig 3a). Serial sections stained
with antiplatelet glycoprotein Ib (GP Ib; Fig 3b)
confirmed the identity of platelets at these sites. In some
sections, relatively large platelet thrombi were identified at this
time (Fig 3c). At later time points, a well-demarcated layer of VWF was
observed on the luminal surface, especially at 30 minutes and day 1;
and there was a progressive shift of positive staining from the lumen
to the outer media from day 1 to day 7 (Figs 3, d-f).
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DBA lectin showed that the endothelium was denuded by
balloon injury but was returning by day 7 and was confluent by day 42.
Measurement of PCNA illustrated that peak vascular smooth muscle cell
division occurred at day 7 and preceded the maximum area of
neointima formation that was recorded on day 21 after
angioplasty (Table 1
).
In addition, regrowing endothelial cells appeared to
contain punctuate and granular VWF at days 12 and 21 (Fig 3, g-i), but
this was not evident in the later preparations (day 42, Fig 3j) when
the monolayer had returned to confluence. Sections of carotid artery
were also examined 3 to 5 cm proximal and 2 to 3 cm distal to the
balloon site. In these instances, VWF was detected strongly on the
luminal surface from 30 minutes to day 7 (Fig 4), even though the
endothelium remained substantially intact and
disturbances of the monolayer were restricted to small isolated
areas. The staining reaction was diminished at day 12 and was negative
by day 21. In comparison with the actual site of angioplasty, VWF was
less marked in the subendothelial layers of the
proximal and distal regions.
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Discussion |
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This study has focused on the distribution of VWF in the blood vessel wall during neointima formation after balloon angioplasty in porcine carotid arteries. Intimal thickening in arteries may predispose to atherosclerosis,37 and acute proliferative responses to vascular injury induced by balloon catheters are thought to govern mechanisms of restenosis.38 39 It may be reasonable to assume therefore that molecules involved in the formation of neointima after tissue injury may commonly contribute to both atherosclerosis and restenosis.8
Many important advances in the knowledge of neointimal progression have been derived from studies in animals subjected to balloon catheter angioplasty. The technique inevitably leads to endothelial denudation, the exposure of thrombogenic surfaces, and the initiation of platelet adhesion, aggregation, and disruption.5 8 40 We have previously utilized the porcine model to quantify the time course of neointima formation after balloon angioplasty and have demonstrated that the technique led to two distinct kinds of injury observed also in clinical studies, namely medial dilatation or deep medial tearing with rupture of the elastic lamina.36 Earlier observations have also demonstrated that macrophage infiltration occurs at the site of angioplasty. The peak inflammatory response occurs at day 3, declines by day 7, and is almost undetectable by day 21. Infiltrating cells were located in both the intima and the media.41 In the current studies, platelets were readily identified by immunohistochemical staining using specific antibodies to porcine VWF and GP Ib and were seen to have rapidly adhered and aggregated on the vessel wall of the injured carotid artery. We were not able to identify platelets 24 hours after angioplasty although an earlier investigation demonstrated the presence of adherent platelet thrombi in some areas up to 5 days after balloon injury in this model.42 The porcine species was found to be especially useful for these purposes since, unlike in other animals, VWF was not present in normal carotid artery endothelium but was abundantly identified after the traumatic procedures. Initial platelet reactions, including the formation of overt platelet thrombi, were followed within 30 minutes by a marked, homogeneous deposition of VWF onto the luminal surface. This persisted for several days and appeared to be progressively translocated to subendothelial compartments. It appeared likely that the origin of this VWF was at least in part derived from platelets, but it is noteworthy that similar appearances were observed in areas of the carotid artery distal and proximal to the site of angioplasty. The distances between the sampling points of the proximal and distal sites from the angioplastied area were relatively large, and endothelial injury was expected to be minimal in these segments of blood vessels adjacent to the balloon site. We recognized, however, that proximal sections were exposed to potential trauma by passage of the catheter and that distal sections could be traumatized by the catheter guidewire. Special care was taken to avoid this; however, small isolated areas of endothelial loss were observed, and some perturbation of the luminal surface was evident even at sites distal to those exposed to the guidewire.43 Nevertheless, the endothelial monolayer remained substantially intact, and rapid platelet adhesion and aggregation were not readily apparent. Additional studies are in progress to clarify the mechanisms of this wider endothelial damage and to determine whether VWF was absorbed from circulating plasma onto the vessel walls in these circumstances.
The presence of VWF in the extracellular matrix in the current study contrasted to the results of others using different animal models. Sussman and Rand12 reported that subendothelial VWF in rabbit aortas was always closely associated with the internal elastic lamina and that deposition of VWF in neointima after balloon angioplasty was dependent on the presence of viable endothelial cells. Similarly, Kockx et al14 demonstrated that VWF was deposited in the subendothelial spaces of intact blood vessels during cuff-induced neointima formation in rabbit carotid arteries and suggested that this was a consequence of enhanced synthesis by endothelial cells and not a result of platelet activation. In contrast, Reidy et al13 showed that injury to rat aortic endothelium, either by balloon catheterization or by treatment with endotoxin, resulted in increased synthesis of VWF by regenerating endothelial cells. Deposition of VWF in subluminal compartments was detected, however, only after balloon catheter denudation of the endothelium, when the lumen was covered by platelets and smooth muscle cells. The precise reasons for the different findings have not been determined, but they may be species related or they may be due to particular physiologic properties of blood vessels from different anatomical sites. It is known, for example, that blood vessels in the rat have unique characteristics8 and that endothelial cells of different tissues and organs in many species are functionally heterogeneous.44 Nevertheless, the variable presence of VWF in the subendothelial matrix under different environmental conditions is in keeping with the concept that this protein plays a central role in platelet-vessel wall interactions leading to occlusive arterial thrombosis after endothelial injury45 and might contribute to diverse mechanisms of cell adhesion, migration, and multiplication.14 Furthermore, biochemical homologies have been identified between specific domains within VWF and other glycoproteins involved in cell-cell interactions.15 16 17 18 19 20 21 22 The present findings are in keeping with the concept that VWF plays a broad functional role in cell biology.24 46
An additional intriguing observation in the present study was that endothelial cells regenerating on the luminal surface of the denuded porcine carotid artery 12 to 21 days after balloon catheterization contained granular and punctuate VWF typically observed in normal undamaged blood vessels obtained from other species.13 14 The appearances were strikingly different from those of control intact porcine carotid artery or denuded artery 6 weeks after catheterization, when VWF was consistently absent.27 28 29 30 It appears unlikely that the VWF-containing cells at the balloon site were macrophages or modified smooth muscle cells, and the findings suggest very strongly that regenerating porcine carotid arterial endothelium transiently expresses VWF within a pattern consistent with its containment within Weibel-Palade bodies. The staining pattern at the site of angioplasty was also different from that of the adjacent but remote segments of blood vessel, where endothelium appeared largely undamaged. The results indicate that the systemic arterial endothelium under these circumstances adsorbs VWF from the circulating plasma or surrounding structures. The results also suggest that intracellular VWF metabolism is regulated by the prevailing local environment and that VWF synthesis, storage, and secretion in replicating endothelial cells on the damaged porcine arterial wall is restricted to a definitive time scale. Endothelial cells in culture are believed to alter their phenotype at confluence and to exhibit the characteristic known as "contact inhibition."47 48 49 It appears possible, therefore, that VWF expression in porcine endothelial cells in vivo is controlled by intracellular signals related to contact-activated growth arrest. VWF was not found, however, at any time in endothelial cells from carotid artery grown in culture, indicating that the regulation of synthesis was probably not dependent simply on active cell growth. Experiments are continuing in an attempt to define the genetic control of VWF synthesis in porcine vasculature. The results have further highlighted the potential value of the porcine model to study the nature of VWF-related mechanisms in vivo and suggest that VWF might play a more general role in vascular repair processes than was previously thought.
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Acknowledgments |
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This work was supported by a grant from the British Heart Foundation. We thank Cerri James for expert secretarial assistance and the Media Resources Centre of the University of Wales College of Medicine for the color illustrations.
Received December 20, 1996; accepted March 4, 1997.
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