© 2000 American Heart Association, Inc.
Integrative Physiology |
Role of Vascular Cell Adhesion Molecule-1 and Fibronectin Connecting Segment-1 in Monocyte Rolling and Adhesion on Early Atherosclerotic Lesions
From the Department of Biomedical Engineering, University of Virginia, Health Science Center, Charlottesville, Va.
Correspondence to Klaus Ley, MD, Department of Biomedical Engineering, University of Virginia, Box 377, Health Science Center, Charlottesville, VA 22908. E-mail kfl3f{at}virginia.edu
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Abstract |
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Abstract—Atherosclerotic lesion development seems to be inflammatory in nature and involves the recruitment of monocytes to the vessel wall. In this study, we investigated the role of vascular cell adhesion molecule-1 (VCAM-1) and fibronectin (FN) connecting segment-1 containing the amino acid sequence ILDV as functional ligands for
4ß1 integrin (VLA-4) in monocyte rolling
and adherence to early atherosclerotic lesions. Carotid arteries of
apolipoprotein E–deficient mice were isolated and perfused with
monocytes or U937 cells. Cell adhesion was reduced 95±4% by
monoclonal antibodies HP1/2 and HP2/1, which block VLA-4 binding to
both VCAM-1 and FN connecting segment-1. mAb HP1/3 preferentially
blocked interaction of VLA-4 with FN but not VCAM-1 and decreased
adhesion by 30±8%. In contrast, blocking VCAM-1 by perfusing the
isolated carotid artery with mAb MK-2.7 reduced adhesion by 75±12%.
Mononuclear cell adhesion to the early atherosclerotic
endothelium was inhibited by 68±10% in the presence
of EILDVPST but not in the presence of control peptide EIDVLPST. When
VLA-4 or VCAM-1 was blocked, more mononuclear cells rolled on early
lesions at significantly higher (approximately doubled) rolling
velocities. These data demonstrate that (1) blockade of VCAM-1 can
abrogate the majority (75±12%) of VLA-4–dependent monocyte adhesion
on early atherosclerotic endothelia and (2) ILDV peptide interferes
with VLA-4 binding to both VCAM-1 and FN and may be useful in limiting
monocyte adhesion to atherosclerotic lesions. (Circ
Res. 2000;87:153-159.)
Key Words: atherosclerosis • monocyte • fibronectin • connecting segment-1 • vascular cell adhesion molecule-1
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The development of an atherosclerotic lesion requires a complex interplay between mononuclear cells, endothelia, vascular smooth muscle cells, growth factors, and cytokines.1 An established atherosclerotic lesion forms through a sequence from fatty streak to fibrofatty matrix and fibrous plaque.2 During this series of stages, monocyte rolling and adhesion to the vascular endothelial lining and subsequent diapedesis are not only the first steps, but also seem to be crucial events in the pathological process.3 The importance of monocyte recruitment to the endothelium of a lesion area is supported by several recent studies. In these studies, formation of atherosclerotic lesions was found to be significantly decreased in mutant mice that do not express macrophage colony-stimulating factors,4 monocyte chemoattractant protein-1,5 monocyte chemoattractant protein-1 receptors,6 7 or interleukin-8 receptors.8 Other mutant mice that do not express one or two adhesion molecules contributing to monocyte recruitment, such as P-selectin, E-selectin, or intercellular cell adhesion molecule-1 (ICAM-1),9 10 11 12 can form atherosclerotic lesions, but they do so at a reduced degree compared with wild-type mice.
At least 4 families of adhesion molecules, selectins, selectin ligands,
integrins, and immunoglobulin-like molecules have been shown to
contribute to the interaction of leukocytes with the
endothelium. For monocytes,
4ß1 integrin (VLA-4)
is a major ligand mediating rolling and firm adhesion of monocytes to
the endothelium.13 In vitro
studies14 and our previous study in the isolated perfused
carotid artery of apolipoprotein E–deficient
(apoE-/-)
mice15 have defined a role of VLA-4 in mononuclear cell
rolling on the endothelium.
There are 2 known ligands for VLA-4. VLA-4 binds to sites within the first and forth immunoglobulin-like domains of the full-length 7-domain form of vascular cell adhesion molecule-1 (VCAM-1).16 VCAM-1 is highly expressed on endothelia prone to develop atherosclerosis in such atherosclerotic models as apoE-/- mice, LDL receptor–deficient mice (LDLR-/-) mice, and rabbits fed with an atherogenic diet.17 18 19 Another ligand for VLA-4 is fibronectin (FN). VLA-4 recognizes a motif containing the sequence EILDVPST within the alternatively spliced connecting segment-1 (CS-1) region of FN,20 with the LDV sequence being most critical.21 Although FN serves mainly as an extracellular matrix component, recently it has been shown that FN CS-1 expression is increased on cultured endothelial cells activated with minimally modified LDL and on the atherosclerotic endothelium of human coronary arteries.22 In a reconstituted in vitro system, isolated VCAM-1, but not FN, coated on the lower wall of a flow chamber can support VLA-4–dependent cell adhesion under flow conditions.23
The binding sites on VLA-4 for VCAM-1 and FN are very close to each other or overlapping, but they have some functional differences. For example, VLA-4 interaction with VCAM-1 is supported by calcium ions but VLA-4 interaction with FN is not.24 Some antibodies preferentially inhibit only the adhesive interaction between VLA-4 and FN.25 Antibody cross-blocking and competitive binding studies show that the two binding sites overlap but are not identical.26 An alternative interpretation of these results25 is that the VCAM-1 and FN binding sites may indeed be identical, but the binding affinity of VLA-4 for FN could be lower. In either case, mAb HP1/3 is a useful reagent to preferentially block cell binding to FN. Short peptides from the CS-1 region of FN have been used to block leukocyte-endothelium interactions27 and diminish VLA-4–dependent inflammatory reactions and formation of atherosclerotic lesions.28
Although some data suggest an involvement of FN CS-1 in the development of atherosclerosis,22 it is unclear whether FN CS-1 serves as a functional ligand for VLA-4 and is important for monocyte rolling and adhesion in atherosclerotic lesions. Moreover, the functional role of VCAM-1 in firm adhesion is unclear.15 In the present study, we used isolated carotid arteries from apoE-/- mice. These mice develop spontaneous atherosclerotic lesions in the arterial vasculature, with advanced lesions morphologically similar to those seen in humans.29 30 We perfused the mice ex vivo to study the molecular basis of mononuclear cell adhesion to early atherosclerotic endothelium. In a previous study,15 we showed that mononuclear cell rolling in the apoE-/- atherosclerosis-prone mouse strains is largely P-selectin– and PSGL-1–dependent. Here, we used specific function-blocking monoclonal antibodies against VCAM-1, FN binding site of VLA-4, and ILDV peptides to directly demonstrate the roles of VCAM-1 and FN CS-1 in monocyte rolling and adhesion on early atherosclerotic lesions.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Monoclonal Antibodies and Peptides
HP1/3 (anti-
4 epitope A, blocking FN
binding to VLA-4), HP2/1 and HP1/2 (anti-4
epitope B1, blocking both FN and VCAM-1 binding
to VLA-4), Lia (anti-4, nonblocking) were
gifts from Dr Sanchez (Universidad Autonoma de Madrid, Madrid, Spain).
mAb MK-2.7 (rat anti-mouse VCAM-1:IgG1, ATCC) was purified from
hybridoma supernatants. CS-1 peptide, EILDVPST, and EIDVLPST control
were prepared by the University of Virginia Biomolecular Research
Facility, dissolved in DMSO, and diluted in MOPS-buffered
physiological salt solution with 1% human serum
albumin.
Cells
The human monocytic leukemia cell line U937 (stably transfected
with human L-selectin [gift from Dr G.S. Kansas, Northwestern
University, Evanston, Ill]) was maintained in RPMI-1640 supplemented
with 10% FBS (Atlanta Biologicals), glutamine (2 mmol/L),
penicillin (100 U/mL), and streptomycin (100 µg/mL) (Gibco BRL).
Human blood monocytes were isolated from leukocyte-rich plasma obtained from healthy donors using hyperosmotic NycoPrep 1.068 density gradient centrifugation (Nycomed). Platelets were removed by centrifugating the monocyte suspension at 300g, yielding pure (>90%), unactivated monocytes.
Animals
Male homozygous
apoE-/- mice were from at
least a fifth generation backcross onto a C57BL/6J background and
obtained from Jackson Laboratory (Bar Harbor, Maine). At 6 weeks of
age, mice were placed on a Western-type diet (21% fat, 0.15%
cholesterol wt/wt [Teklad Adjusted Calories Diet TD 88137,
Harlan Teklad]) for 4 to 5 weeks. As previously
described,15 the carotid artery was perfused with
heparinized MOPS-buffered physiological salt
solution supplemented with 1% human serum albumin at 10
µL/min, resulting in a perfusion pressure of 30 to 60 mm Hg and
a wall shear stress of 3.0±0.1 dyne/cm2. U937
cells or monocytes labeled with calcein AM were infused at
3x106 cells/mL. To block VCAM-1, carotid
arteries were perfused with 1 mL of a 40 to 50 µg/mL mAb MK-2.7
solution for 10 to 15 minutes. Cell rolling and adhesion were
recorded on videotape using stroboscopic epifluorescence
illumination with an intravital microscope. At the end of each
experiment, endothelial integrity of the isolated
carotid artery was assessed by Evans Blue staining.
Flow Cytometry
U937 cells at 3x106 cells/mL were stained
by monoclonal antibodies (mAbs) at different dilutions for 30 minutes
at room temperature, washed twice, incubated with antimouse FITC-IgG,
fixed in 1% paraformaldehyde and PBS, and
analyzed by flow cytometry on a FACScan (Becton Dickinson).
Immunohistochemistry
VCAM-1 and ICAM-1 expression was determined on paraffin sections
(5 µm thick) of murine common carotid artery blocked with 10%
horse serum (Vector Laboratories) and incubated with primary antibody
(polyclonal goat antimouse VCAM-1 or polyclonal goat antimouse ICAM-1,
5 µg/mL, Santa Cruz Biotechnology, Inc) overnight at 4°C followed
by biotin-conjugated horse antigoat antibody, avidin-biotin
complex, and 3, 3'-diaminobenzidine as substrate (Vector
Laboratories).
Statistical Analysis
Rolling flux and the number of adherent cells are mean±SEM.
Comparisons between groups were performed by using a two-way ANOVA,
followed by analysis using the Tukey-Kramer multiple comparison
test. The rolling velocity distributions were compared using the
Mann-Whitney U test. All statistical analysis was
performed with the NCSS software package.
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Results |
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Rolling and adhesion of mononuclear cells (U937) and monocytes were investigated under flow conditions (3 dyne/cm2) in carotid arteries obtained from apoE-/- mice fed a Western diet for 4 to 6 weeks. Rolling in this model requires interaction of endothelial P-selectin with PSGL-1 expressed on the monocyte surface.15 In this study, we investigated the molecular mechanism of monocyte arrest.
Expression of Adhesion Molecules
Carotid arteries harvested from apoE–/–
mice expressed VCAM-1 and ICAM-1 along the endothelial
lining but not in the media or adventitia (data not shown). This
confirms recent data obtained by Nakashima et al.17 The
intima and media did not contain significant numbers of
macrophages, as shown by insignificant staining for the
macrophage marker F4/80 (data not shown). Age-matched C57BL/6
mice did not show expression of either ICAM-1 or VCAM-1 (data not
shown). These findings suggest that expression of
endothelial ICAM-1 and VCAM-1 reflects the earliest
changes in the endothelial lining before the
development of atherosclerotic lesions.
The U937 cells used in this study expressed significant amounts of
4 integrins (Figure 1
). Saturation of binding sites for mAbs
Lia, HP1/2, and HP1/3, all recognizing 4, were
achieved at a concentration of 1:100 (Figure 1), and this
concentration was used for all function-blocking experiments. We also
found expression of LFA-1, Mac-1, and the common ß chain, CD18,
expressed on U937 cells (Figure 1).
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Mononuclear Cell Adhesion Under Flow
In a previous study,15 we showed that U937 cells do
not roll or adhere in carotid arteries obtained from wild-type C57BL/6
mice fed a chow diet. In carotid arteries from
apoE-/- mice fed a
Western diet, U937 cell rolling and adhesion under flow require
P-selectin and PSGL-1. Monocytes or U937 cells accumulated around the
bifurcation area (Figure 2), which
represents a known lesion-prone site in
apoE-/- mice, as
described earlier.3 Incubation of U937 cells with mAb
HP1/2 to VLA-4 integrin almost completely abrogated their accumulation
on the lesion-prone endothelium (Figure 2). The
number of adherent cells was sharply reduced at the end of a 5-minute
period of perfusion when treated with mAb HP2/1 to VLA-4 or mAb MK-2.7
to VCAM-1 but not when treated with control antibodies (Figure 3). To investigate the dynamics of
mononuclear cell adhesion, we recorded cell accumulation during
each minute after the onset of cell perfusion for 5 minutes (Figure 4). The dramatic reduction of mononuclear
cell accumulation caused by ILDV peptide, mAb MK-2.7, or mAb HP2/1 was
evident as early as 1 minute after the start of perfusion (Figure 4).
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To investigate the nature of the endothelial ligand for
VLA-4 integrin, we perfused carotid arteries from
apoE-/- mice with mAb
MK-2.7, a function-blocking antibody to VCAM-1. This treatment also
sharply reduced accumulation of U937 cells by 80% and was almost as
efficient as blocking VLA-4. VLA-4 can also bind to an alternatively
spliced form of FN containing the sequence ILDV, which may be expressed
on the surface of atherosclerotic endothelial
cells.22 When we perfused U937 cells through carotid
arteries obtained from
apoE-/- mice in the
presence of ILDV-containing peptide, we found significant inhibition of
cell accumulation, similar to the effect of blocking VCAM-1 or VLA-4.
Control peptide containing the inverted sequence, IDVL, had no
significant effect. Because blocking VCAM-1 with mAb MK-2.7 had no
additional effect beyond that seen with ILDV peptide (data not shown),
we conclude that, as in previous studies,26 ILDV peptide
binds to VLA-4 in a position that blocks VLA-4 binding to both FN and
VCAM-1. Next, we used another antibody, mAb HP1/3, that preferentially
blocks its binding to FN but not to VCAM-1.25 HP1/3
consistently blocked 
20% to 30% of U937 cell adhesion to
the surface of isolated perfused carotid arteries. A binding control
antibody, mAb Lia, bound to an epitope of 4
not involved in ligand binding and had no effect.
To confirm these findings for primary monocytes, we perfused isolated
carotid arteries of
apoE-/- mice with fresh
human monocytes isolated from peripheral blood. As shown in
Figure 5, these cells accumulated at a
similar rate as U937 cells. Accumulation was significantly blocked by
VLA-4–blocking mAb HP1/2 or by VCAM-1–blocking mAb MK-2.7. Taken
together, these findings show that mononuclear cell adhesion to
atherosclerosis-prone endothelia in the isolated
perfused carotid artery is almost completely dependent on VLA-4
integrin, which binds mostly (70% to 80%) to VCAM-1 and shows a small
but consistent (20% to 30%) contribution of alternatively
spliced FN.
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Impact of VLA-4 and Its Ligands on Rolling Flux and
Velocity
In a previous study,15 we showed that blocking either
VLA-4 integrin or VCAM-1 increased rolling velocities to a similar
extent. The impact of these molecules on rolling flux was unclear,
because blockade of VLA-4 integrin reduced rolling flux in carotid
arteries of wild-type C57BL/6 mice fed a Western-type diet but
increased rolling flux in carotid arteries from
apoE-/- mice under the
same conditions.15 Therefore, we reexamined the role of
VLA-4 integrin and VCAM-1 more thoroughly.
All manipulations blocking VLA-4 or VCAM-1, mAb HP2/1, mAb MK-2.7, or
LDV peptide, but not mAb HP1/3s blocking 4
integrins binding to CS-1 peptides only, caused a significant increase
in the number of rolling U937 cells (Figure 6). We confirmed that this rolling was
P-selectin– and PSGL-1–dependent15 (data not shown). The
increased rolling flux after blockade of 4 or
VCAM-1 was probably a direct consequence of the reduced number of
adherent cells. This can be seen by comparing the numbers in Figure 6 with the accumulation numbers in Figure 4
, which
suggests that the cells that cannot adhere when VLA-4 or VCAM-1 is
blocked continue to roll.
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We confirmed that blocking VLA-4 by mAb HP1/2 or blocking VCAM-1 by mAb
MK-2.7 significantly elevated the velocity of rolling mononuclear cells
in this model (Figure 7), elevating mean
rolling velocity from 106±52 µm/s to 293±86 µm/s and
227±77 µm/s, respectively (P<0.01). Treating the
U937 cells with HP1/3 also caused a small increase in rolling velocity,
from 106±52 to 135±49 µm/s (P<0.01). We extended
these findings by investigating the impact of FN-derived peptides.
LDV-containing peptides also significantly elevated rolling velocity
(Figure 7), whereas the control peptide containing the inverted
sequence, DVL, had no effect.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Our data show that U937 cell adhesion to carotid arteries isolated from atherosclerosis-prone mice before the development of manifest lesions is mediated by VLA-4 binding to VCAM-1, with a minor contribution of alternatively spliced FN as an alternative VLA-4 ligand. This functional finding is supported by morphological demonstration of VCAM-1 expression on sites prone to develop lesions but not on normal endothelium.
Several studies have shown VCAM-1 expression on endothelia at atherosclerotic lesions of humans,31 mice,17 and rabbits18 ; however, functional data are limited.28 Adhesion assays using cultured endothelial cells activated by cytokine treatment showed a major contribution of VCAM-1 to monocyte adhesion.14 This is in contrast to findings in cultured endothelial cells treated with minimally oxidized LDL and specific oxidized lipids,22 32 where almost all monocyte adhesion was mediated by alternatively spliced FN, and VCAM-1 was not expressed at significant levels. This apparent discrepancy is most likely due to differences in the models used. First, cultured endothelial cells are known to be much more permeable to solutes than endothelia in situ.33 Specifically, significant gaps exist between cultured endothelial cells,34 through which extracellular matrix material containing FN may be exposed to the luminal surface. The lack of VCAM-1 expression in endothelial cells treated with minimally oxidized LDL22 32 and the presence of VCAM-1 on the endothelial surface of carotid arteries obtained from atherosclerosis-prone mice suggest that the treatment with oxidized LDL may only incompletely mimic the pathophysiological process of endothelial activation in atherosclerosis in vivo. In atherosclerotic lesions, both cytokines35 and chemokines36 have been detected in addition to oxidized lipoproteins. The profile of adhesion molecule expression in our model is likely to result from a combination of these and other potential factors.
The crucial roles of VLA-4 and VCAM-1 demonstrated in our ex vivo model are supported by in vivo expression data17 18 and peptide-based in vivo experiments.28 Gene-targeting experiments showing the importance of VLA-4 and VCAM-1 for atherosclerotic lesion development have been hampered by the unavailability of appropriate knockout mice. Null mutations for VCAM-137 38 and FN39 all lead to embryonic lethality so that no adult mice are available to study the impact of these molecules on atherosclerosis. Recently, a VCAM-1 hypomorphic mouse has been developed, which holds promise for additional clarification of the role of VCAM-1 for atherosclerosis in vivo (H. Li, M. Chen, M. Liyama, J.-C. Gutirrez-Ramous, D.S. Milstone, M.I. Cybulsky, unpublished data). Cell-specific and inducible strategies have been developed that seem able to eliminate VCAM-1 only in endothelial cells or eliminate VLA-4 only in monocyte macrophages; however, these strategies have met with significant technical problems, and no informative gene-targeted mice with conditional mutations in VLA-4 or VCAM-1 are available at this time.
In conclusion, our study links expression of VCAM-1 in early atherosclerotic lesions17 and the shoulder region of established atherosclerotic lesions18 to a crucial function in mononuclear cell adhesion and accumulation. This link provides a mechanistic basis for understanding the ability of LDV-containing peptides28 to curb the development of atherosclerotic lesions in animal models. Our study suggests that interfering with VLA-4 binding to VCAM-1 prevents the adhesion of monocytes with the vascular endothelium under flow conditions typical of recirculation zones and zones of disturbed flow where atherosclerotic lesions develop in vivo. These findings strengthen the rationale for the development of therapies aimed at inhibiting the interaction between VLA-4 and VCAM-1 to prevent the development of atherosclerotic lesions and their complications.
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Acknowledgments |
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This work was supported by the National Institutes of Health grant HL-58108 (to K.L.). We wish to thank the Biomolecular Research Facility at the University of Virginia for synthesizing the LDV and DVL peptides and producing the mAb from hybridomas. We thank William Ross for help with flow cytometry, John Sanders and David Manka for immunostaining, Markus Sperandio for statistical analysis, and Nicholas Douris and Jennifer Bryant for mouse husbandry.
Received February 3, 2000; accepted May 23, 2000.
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