© 1998 American Heart Association, Inc.
Original Contributions |
Upregulation of VCAM-1 and ICAM-1 at Atherosclerosis-Prone Sites on the Endothelium in the ApoE-Deficient Mouse
From the Department of Pathology, University of Washington, Seattle (Y.N., E.W.R., R.R.); and the Laboratory of Biochemical Genetics and Metabolism, The Rockefeller University, New York, NY (A.S.P., J.L.B.).
Correspondence to Russell Ross, PhD, Department of Pathology, University of Washington School of Medicine, 1959 NE Pacific St, Box 357470, Seattle WA 98195-7470. E-mail rross{at}u.washington.edu
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Abstract |
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Abstract—Focal recruitment of monocytes and lymphocytes is one of the earliest detectable cellular responses in the formation of lesions of atherosclerosis. This localized accumulation of leukocytes is a multistep process in which the endothelium remains intact and may regulate leukocyte recruitment by expressing specific adhesion molecules. To examine the relationship of adhesion molecule expression to initiation factors and the sites of lesion formation, we analyzed the expression of vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1), and platelet–endothelial cell adhesion molecule-1 (PECAM-1) en face on the aortic endothelium of control mice and homozygous apolipoprotein E–deficient (ApoE -/-) mice that develop complex lesions of atherosclerosis similar to those in humans. In control mice, VCAM-1 staining was weak and limited to sites of altered blood flow. In contrast, in the ApoE -/- mice, VCAM-1 appeared to be localized over the surface of groups of endothelial cells in lesion-prone sites. Expression of VCAM-1 preceded lesion formation, and increased expression above control levels appeared to be correlated with the extent of exposure to plasma cholesterol. Although ICAM-1 was the most prominent adhesion molecule in lesion-prone sites, its expression appeared to be independent of plasma cholesterol levels and was upregulated in both ApoE -/- and control mice. At lesion-prone sites associated with altered blood flow, ICAM-1 was located over the surface of each endothelial cell and on microvilli, whereas VCAM-1 was confined to the cell periphery in non–lesion-prone sites. PECAM-1 was localized at the cell periphery throughout the aorta, and its expression did not appear to be regulated. Thus, the levels, localization, and characteristics of expression of VCAM-1, ICAM-1, and PECAM-1 appear to be differentially regulated. Upregulation of VCAM-1 and ICAM-1 is associated with sites of lesion formation.
Key Words: transgenic mouse • monocytes • PECAM-1 • adhesion • microvilli
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Introduction |
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One of the earliest detectable cellular responses in the formation of lesions of atherosclerosis is leukocyte adherence to the endothelium at particular anatomic sites in the artery wall.1 2 3 As in other inflammatory responses, the leukocytes migrate across the EC barrier and accumulate in the subendothelial space, where some of the monocytes ingest lipid and become foam cells. However, atherosclerosis appears to be a specialized inflammatory response in which leukocyte recruitment occurs in lesion-prone areas of the arterial tree and results in subendothelial accumulation of monocytes and lymphocytes without granulocytes. This recruitment of specialized leukocytes persists so long as the condition of hypercholesterolemia continues in the subject. During that time, the vascular endothelium remains intact and participates in recruitment of leukocytes by expression of specific leukocyte adhesion molecules.
Distinct adhesion molecules appear to regulate different stages of leukocyte immigration at inflammatory sites in a multistep process.4 The current model, based primarily on studies of neutrophils, suggests that emigration is regulated by at least three discrete molecular signals, which appear to act together or in sequence. The first step includes a primary and transient adhesion event, which allows "sampling" of the endothelial surface. In this step, endothelial P- and E-selectins, which bind carbohydrate ligands on leukocytes,4 and the leukocyte integrin very late–acting antigen-4 interact with endothelially expressed VCAM-1.5 6 7 8 The first step, which allows flowing cells to tether and subsequently roll along the vessel wall, is followed by the second step, a rapid, activating event that increases adhesion and arrests the cell. Chemoattractants released from the tissue or localized on the surface of the endothelium transduce signals that activate integrin adhesiveness. Members of the immunoglobulin superfamily of endothelial adhesion molecules, including ICAM-1 and VCAM-1, mediate firm adhesion. In the final step, chemotaxis and transmigration take place across the endothelial lining into the tissue. Another member of the immunoglobulin superfamily, PECAM-1/CD31, is required for leukocyte transendothelial migration in vitro9 and in vivo.10
In this study, the thin and transparent aorta of the mouse made it possible to qualitatively evaluate the adhesion molecules expressed on the surface of the endothelium of the entire aorta by the use of whole-tissue mounts and in situ immunocytochemistry. Different time points were evaluated in ApoE -/- mice, in which a dramatic increase in plasma cholesterol levels is associated with spontaneous development of atherosclerosis, including fibroproliferative lesion formation.11 12 13 14 We compared specific anatomic sites of lesion development with the location of adhesion molecule expression. Adhesion molecules involved in all three steps of leukocyte recruitment have been evaluated: VCAM-1, which together with P- and E-selectin, is involved in the first step of tethering and rolling of monocytes and lymphocytes and in second-stage arrest and firm adhesion; ICAM-1, which helps mediate arrest and firm adhesion of lymphocytes, monocytes, and neutrophils; and PECAM-1, which appears to be involved in transendothelial cell migration. Our studies demonstrate that blood flow and plasma cholesterol levels appear to differentially regulate these three adhesion molecules and particularly support a role for VCAM-1, when it localizes at lesion-prone sites that manifest increased ICAM-1, in focal recruitment of monocytes and lymphocytes in developing lesions of atherosclerosis.
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Methods |
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Reagents
The sources and working dilutions of both primary antibodies and irrelevant control immunoglobulins are listed in the Table
. Using a cell-surface ELISA, Hahne
et15 al showed that antibodies to VCAM-1 and
ICAM-1 react with antigens expressed on the surface of a mouse
endothelioma cell line. Biotinylated rabbit anti-rat IgG (heavy and
light chain) was obtained from Vector Laboratories, Inc. The 10-nm
gold–labeled goat anti-rat IgG (H+L), 10-nm gold–labeled
streptavidin, and IntenSETM M silver enhancement kit were obtained from
Amersham Corp. Normal mouse serum was obtained from Zymed
Laboratories, Inc.
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ApoE -/- and Control Mice
Homozygous ApoE -/- male mice, second- or third-generation
hybrid 129olaxC57BL/6, were derived from brother-sister matings. We
used only ApoE -/- animals initially created by homologous
recombination in embryonic stem cells.11 C57BL/6
mice (The Jackson Laboratory, Bar Harbor, Me) were used as controls.
Animal diet and experiment schedules are shown in Figure 1. Both the ApoE -/- and control mice
were weaned at 4 weeks of age and maintained on a chow diet (PicoLab
Rodent Chow 20, 4.5% fat by weight, 0.02% cholesterol).
After 1 week (ie, at 5 weeks of age), 6 ApoE -/- and 6 control
(C57BL/6) mice were killed. After 2 weeks (at 6 weeks of age), 12 ApoE
-/- and 12 control mice were changed to a Western-type diet (Teklad
Adjusted Calories Western-type diet, 21% fat by weight, 0.15%
cholesterol, 19.5% casein without sodium cholate). The
remaining 36 animals (24 ApoE -/- and 12 control mice) were
maintained on chow. Diet and water were provided ad libitum. The
animals were perfusion fixed with 4% paraformaldehyde
for 30 minutes. The heart and aorta were then removed and immersion
fixed in 4% paraformaldehyde overnight. The aortic
sinus, ascending aorta, aortic arch, and abdominal aorta were dissected
along a lateral margin. When the aorta was dissected, the surrounding
tissue was carefully removed. After the lumen was opened, the aorta was
flattened onto a silane-coated slide with superglue (Loctite Corp) to
attach each specimen endothelium side up. To allow
examination of the aortic sinus on a flat specimen, we dissected away
the cusps of the three valves to expose the base of each valve.
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In Situ Immunocytochemistry
Staining for each of the adhesion molecules was performed in at
least 2 animals from each group and at each time point; specimens were
examined by light and electron microscopy. Because the tissues were
prepared differently for light microscopy and scanning electron
microscopy, each time point was represented by 4 to 6
animals in most cases. Immunocytochemistry was performed as follows.
The specimens were blocked with 0.1% goat or rabbit serum in PBS with
1% BSA for 1 hour at RT. They were incubated with the primary antibody
at the concentrations listed in the Table
for 1 hour at RT. A solution
of PBS–1% BSA containing biotinylated rabbit anti-rat IgG (H+L;
dilution, 1:200) and mouse serum (1:100) was applied as a secondary
antibody for 1 hour at RT for VCAM-1 staining. The VCAM-1 specimens
were incubated with PBS–1% BSA containing 10-nm gold–labeled avidin
(1:25) for 1 hour at RT. PBS–1% BSA containing 10-nm gold–conjugated
goat anti-rat IgG (1:25) and mouse serum (1:100) was applied for 1 hour
at RT for ICAM-1 or PECAM-1 staining. Each step was followed by a wash
with PBS performed 3 times. After reaction with the gold-labeled
reagents, the specimens were fixed with half-strength Karnovsky's
solution overnight at 4°C. Next they were washed with distilled water
3 times and processed with silver enhancement (IntenSETM M) for 7 to 12
minutes at RT. Some specimens were mounted with PBS and examined by
light microscopy. The same specimens were observed by scanning electron
microscopy (described below). Other specimens were counterstained with
Harris hematoxylin or methyl green and mounted with Histomount.
Immunoelectron Microscopy
For scanning electron microscopy, the specimens were processed
with silver enhancement, critical-point dried, sputter-coated with
gold-platinum alloy, and observed with the scanning electron microscope
(JSM 35C and JSM 6300F, JEOL). For transmission electron microscopy,
the specimens were not processed with silver enhancement but were
postfixed with osmium, dehydrated with alcohol, and embedded in Medcast
(Ted Pella Inc). Thin sections were stained with lead citrate and
uranyl acetate and observed by transmission electron microscopy (JEM
1200E XII, JEOL).
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Results |
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The Aortic Arch and Branching Sites of Major Arteries Are Lesion Prone in ApoE-/- Mice
At 5 weeks of age, the aorta of the ApoE -/- mouse contained a few, small, isolated lesions, which were detectable by examination with a dissection microscope. By 8 weeks of age, slightly elevated lesions, fatty streaks (by histological examination),13 develop at lesion-prone sites such as the lesser curvature of the aortic arch and the outflow tract of the brachiocephalic artery (Figure 2
).
Under the dissection microscope and illumination with reflected light,
these sites show grossly elevated, opaque, small, white lesions. At 20
weeks of age, many of these lesions have fused to form larger, more
advanced lesions. ApoE -/- mice fed the Western-type diet (plasma
cholesterol levels of 1085 to 4402 mg/dL) have larger
lesions than those fed the chow diet (plasma cholesterol
levels of 360 to 885 mg/dL) for the same period of
time.13 No lesions of
atherosclerosis were observed in the control mice fed
either diet (plasma cholesterol levels of 101 to 119 mg/dL
on chow and 154 to 301 mg/dL on Western-type diet) for these periods of
time.
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VCAM-1 Increases at Lesion-Prone Sites in ApoE -/- Mice
Because VCAM-1, like P- and E-selectin, is involved in the initial
tethering and rolling step5 6 7 8 as well as arrest
and firm adhesion7 16 in the process of leukocyte
infiltration of inflammatory sites, we examined VCAM-1 expression in
control mice of 5, 8, and 20 weeks of age. In control mice, only a few
ECs weakly stained with antibodies to VCAM-1 in the aortic sinus and in
outflow tracts of some small branches of the aorta (Figure 3A). The remainder of the aortas from
control mice had only a few isolated, weakly stained, VCAM-1–positive
cells (Figure 3B). No staining was observed with either control
antibody (data not shown).
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In contrast to control animals, ApoE -/- mice showed markedly
increased VCAM-1 staining on the surface of the ECs in lesion-prone
sites, including the aortic sinus and outflow tracts. At 5 weeks of
age, ApoE -/- mice had a small number of positive cells with
relatively weak staining. By 8 weeks of age, the staining appeared to
be more intense, and more positively stained cells were visible in mice
fed the Western-type diet (plasma cholesterol at 8 weeks,
2148±495 mg/dL) than in those fed chow. Some of the VCAM-1–positive
cells were located over the lesions or at the periphery of the lesion
where no morphological abnormality was observed in the underlying
subendothelial space (Figure 3C). At 20 weeks on the
Western-type diet (plasma cholesterol, 1959±315 mg/dL),
the number of VCAM-1–positive cells increased, and the cells were
located principally in the shoulder region of advanced lesions (Figure 3D and 3E). Although staining was observed over the "dome" of the
lesion, it was weaker than at the shoulder (Figure 3F). As observed at
8 weeks, the number of positive cells appeared to be greater in
the mice fed the Western-type diet than in those fed chow (data not
shown). Thus, VCAM-1 expression has been demonstrated at lesion-prone
sites, and the relative level and extent of expression appear to
increase with hypercholesterolemia.
Electron microscopy revealed a uniform distribution of VCAM-1 on the
smooth surface of each involved EC, with no accentuation at the cell
border (Figure 3G and 3H). In some cases, VCAM-1 was concentrated at
the trailing edge in relation to flow (Figure 3G).
Upregulation of ICAM-1 at Lesion-Prone Sites Is Independent of ApoE
Deficiency or Diet
ICAM-1 is thought to be involved in the firm adhesion step
in leukocyte infiltration. Antibodies to ICAM-1 diffusely stained
individual ECs over the aortic surface in both ApoE -/- and control
mice at 5 and 8 weeks of age. The staining pattern was more intense in
lesion-prone sites, such as the lesser curvature of the aortic arch and
the orifice of the brachiocephalic artery (Figure 4). However, there was little to no
difference either in the pattern of localization or in the intensity of
staining of ICAM-1 between ApoE -/- mice (Figure 4A and 4C) and
control mice (Figure 4B) or between the mice fed the Western-type diet
(Figure 4C) versus the chow diet (Figure 4A). In Figure 4C, the lesser
curvature and the orifice of the brachiocephalic artery appear darker
because the thickness of the lesions makes them appear dark under
transmitted light. Other lesion-prone sites, including the aortic sinus
and branching sites in the abdominal aorta, also stained with
relatively equivalent intensity, with no apparent differences between
ApoE -/- and control mice at these sites or between the time points
examined (data not shown).
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By light microscopy, staining for ICAM-1 was primarily localized over
the surface of each EC at lesion-prone sites (Figure 5A) in both ApoE -/- and control mice.
At non–lesion-prone sites, staining was mainly confined to the cell
periphery (Figure 5B). Exceptions to this distribution were lesions in
ApoE -/- mice at 20 weeks of age, in which ICAM-1 was primarily
localized at the borders of the ECs that covered the dome of the
advanced lesions (Figure 5C), whereas in the shoulder regions of the
lesions, the entire surface of the ECs remained positive for ICAM-1
(Figure 5D). The ECs are more polygonal at lesion-prone sites (Figure 5A), whereas they are spindle shaped in non–lesion-prone sites (Figure 5B), which suggests that blood flow influences both cell shape and
ICAM-1 expression.
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Scanning electron microscopy of lesion-prone sites substantiated the
presence of ICAM-1 over the smooth surface of the plasma membrane and
at the cell periphery (Figure 5E), where numerous microvilli appeared
"decorated" with immune products (Figure 5F and 5G, arrows).
Microvilli were present on the surface of the bulge occupied by the
underlying nucleus and at the cell periphery, and ICAM-1 staining of
the microvilli was observed at both lesion-prone and non–lesion-prone
sites. In non–lesion-prone areas, ICAM-1 was primarily localized at
the cell periphery (Figure 5H), and microvilli were not as prominent
(Figure 5I) as they were at lesion-prone sites (Figure 5F). Many
adherent leukocytes were observed by scanning electron microscopy in
lesion-prone sites throughout the aortas of the ApoE -/- mice. These
leukocytes appeared either as rounded cells, which had no obvious
relationship to the endothelial microvilli, or as
stretched, flattened cells, which were closely associated with
microvilli on the endothelial surface (Figure 6).
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PECAM-1 Is Diffusely Localized Throughout the Aorta
PECAM-1 antibodies blocked transendothelial
migration of leukocytes in vitro and in vivo.9 10
In both ApoE -/- and control mice at 5, 8, and 20 weeks of age,
antibodies to PECAM-1 stained ECs throughout the aorta. As with ICAM-1
staining, there was no apparent difference in staining intensity
between the ApoE -/- mice and the controls. However, in contrast to
ICAM-1, there were no observable differences between lesion-prone sites
and other areas, nor was any difference observed on ECs that covered
the lesions (data not shown). Light microscopy showed that PECAM-1 was
confined principally to the periphery of each cell (Figure 7).
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Hypercholesterolemia-Associated Upregulation of VCAM-1 Suggests a Role in Lesion Formation and Expansion
Of the three adhesion molecules examined in this study, only VCAM-1 was upregulated at lesion-prone sites by hypercholesterolemia. In mice at 5 and 8 weeks of age, VCAM-1 was expressed on ECs that had no foam cells beneath them. Similar observations were made from transverse sections of the aortas of rabbits fed a high-cholesterol diet for 1 week.17 18 These results suggest that VCAM-1 expression is an early event that precedes fatty streak formation and may be important in monocyte recruitment from the blood. In support of this hypothesis, Marui et al19 found that oxidized LDL, thought to be present in the arterial wall with hypercholesterolemia, including in the ApoE -/- mouse,20 induced VCAM-1 but not ICAM-1 expression in cultured ECs.
In ApoE -/- mice at 20 weeks of age, VCAM-1 was localized in the shoulder regions of advanced lesions rather than over the apex of the lesions. This observation is correlated with foam cell accumulation in the shoulder regions of transitional lesions of human atherosclerosis, as pointed out by Daugherty et al.21 Li et al17 also noted that VCAM-1 expression appeared particularly elevated at lesion edges and extended several cells beyond the edge. These same regions showed leukocyte recruitment through an intact endothelial monolayer by scanning electron microscopy. These findings suggest that the shoulder is a locus of monocyte recruitment and the site where lesion expansion occurs. Thus, VCAM-1 appears to play a role in both lesion formation and expansion.
Upregulation of VCAM-1 appears to be limited to the endothelial surface of the aortic sinus and a small area of outflow at branch sites in ApoE -/- and control mice. Davies et al22 observed a higher EC turnover rate in cultured endothelium under turbulent flow compared with those under laminar or no flow. Tanaka et al,23 using balloon injury, suggested that regenerating ECs at the leading edges express VCAM-1. Upregulation of VCAM-1 has also been observed in the rabbit carotid artery in which laminar shear stress was both increased and decreased by surgical manipulation, most significantly with decreased shear.24 Thus, VCAM-1 may be expressed in normal vessels on regenerating ECs and in outflow tracts at branches where decreased laminar shear stress or increased turbulent flow is present.
VCAM-1 Expression at Lesion-Prone Sites May Significantly Impact
Monocyte and Lymphocyte Recruitment
Expression of VCAM-1 appears to increase at lesion-prone sites in
hypercholesterolemic animals. For monocytes and
lymphocytes, cells that accumulate in lesions of
atherosclerosis, VCAM-1 is unique among the three
adhesion molecules examined because it allows tethering and rolling of
monocytes and lymphocytes, as well as firm adhesion and arrest under
physiological conditions, including
flow.5 6 7 25 In vitro data suggest that VCAM-1
may regulate transendothelial migration of monocytes,
especially on activated
endothelium.26 27 28 Although
questions remain regarding the contribution of VCAM-1 to tethering and
rolling,29 involvement of VCAM-1 in the first
step of transient interactions may be particularly important for
immunoblasts or selectin negative memory T lymphocytes, which lack the
ligand for E-selectins that normally regulate the tethering of these
leukocytes to arterial endothelium.
Although we did not examine P- or E-selectin formation in these
studies, both of these molecules may be important in tethering the
cells at sites where ICAM and VCAM are
upregulated.18 VCAM-1 is also unique in its
interaction with very late–acting antigen-4, where firm adhesion is
induced without chemoattractant stimulus.5 6 7 The
possibility that VCAM-1 can spontaneously arrest leukocytes and bypass
the requirement for chemoattractants is provocative,
especially given the expression of VCAM-1 prior to fatty streak
formation and in areas apparently devoid of underlying leukocytes
(Reverences 17 and 18 and vide infra).
ICAM-1 Levels Are Related to Flow
In the present study, there were no apparent differences in
the relative intensity or localization of antibody staining for ICAM-1
in either the ApoE -/- or the control mice. The most intensely
stained areas were the lesion-prone sites, such as the lesser curvature
of the arch and the outflow tracts at branches of major arteries. In
the lesion-prone sites the strongly positive ECs appeared more cuboidal
than did those in the lightly stained non–lesion-prone areas. The
shape of the ECs is related to the level of laminar shear stress. High
shear induces elongation of the ECs in the direction of
flow.30 Thus, increased expression of ICAM-1 on
the more cuboidal cells suggests that decreased shear, or possibly
altered or turbulent flow, may upregulate ICAM-1 expression on the
endothelial surface. ICAM-1 also showed lower levels of
expression on ECs over the domes of the advanced lesions compared with
the ECs that covered the shoulder region, known as the site of
expansion of advanced lesions. Because these changes are in
lesion-prone sites where ICAM-1 is upregulated at earlier time points,
it suggests that local changes in flow or other regulators can decrease
expression within these areas.
ICAM-1 and most of the other adhesion molecules can be regulated by cytokines, but only ICAM-1 is regulated by flow in vitro.31 Resnick et al32 identified a cis-acting shear stress–response element within the promoter of the platelet-derived growth factor-B gene, a potent growth factor and chemoattractant for smooth muscle cells whose expression is increased in lesions of atherosclerosis.33 The shear stress–response element is required for transcriptional upregulation of platelet-derived growth factor-B in ECs exposed to physiological levels of laminar shear stress, and the same shear stress–response element is found within the ICAM-1 promoter region. Nagel et al31 observed that on exposure to laminar shear stress, ICAM-1 is upregulated in cultured ECs in a time-dependent and force-independent manner compared with static conditions. In contrast, VCAM-1 and PECAM-1, which have no shear stress–response element, are not upregulated by mechanical forces in vitro. En face examination of the normal rabbit carotid artery showed extensive upregulation of ICAM-1 with increased laminar shear, whereas reduced shear suppressed its expression.24 Although both the in vitro and in vivo manipulation of flow suggests that increased laminar shear is associated with upregulation of ICAM-1, lesion-prone sites of ICAM-1 expression are areas of decreased laminar shear and increased turbulent flow. Focal expression of ICAM-1 has also been noted in normal human vessels,34 particularly at sites of disturbed flow.35 Thus, the in vivo and in vitro data suggest that biomechanical forces may play a role in regulating ICAM-1 expression on the ECs.
ICAM-1 Localization on the Smooth Surface of the Plasma Membrane
and Microvilli May Also Be Regulated by Flow
By electron microscopy, ICAM-1 is present on both the smooth
surface of the plasma membrane and on microvilli in lesion-prone sites,
areas of apparent decreased shear or turbulent flow. In contrast, at
non–lesion prone sites, ICAM-1 was principally confined to the cell
periphery, and microvilli were not as prominent as at lesion-prone
sites. VCAM-1 and PECAM-1 were also present on some microvilli, but
the numbers of these molecules appear to be qualitatively less frequent
than those of ICAM-1 (data not shown). Carpén et
al36 reported that ICAM-1 was expressed on
microvilli of transfected COS cells and was associated with the
actin-containing cytoskeleton and 
-actinin. Microvillous receptor
presentation is critical for contact initiation under flow
conditions.37 We observed that microvilli are
more frequently associated with adherent, spread leukocytes rather than
with leukocytes having a rounded profile. Others have observed that
blockade of ICAM-1 or ß2-integrin, the ligand for ICAM-1, inhibited
spreading of monocytes on interleukin-4–stimulated ECs in which
VCAM-1 expression is upregulated.25 38
ß2-Integrin is not expressed on microvilli; rather, it is
concentrated on the nonvillous planar cell body of
leukocytes.39 Exclusion of ß2-integrin from
microvilli may ensure its participation in events that follow initial
contact.
En face examination of ICAM-1 distribution in the normal rabbit carotid artery also demonstrated junctional localization,24 similar to our observations in non–lesion-prone sites. Interestingly, reduced shear stress for 5 days in the rabbit carotid artery resulted in a more diffuse distribution of ICAM-1, although lower levels of expression were also observed. Together with our studies, these data suggest that ICAM-1 may be preferentially located on microvilli, and its localization at the cell periphery or over the entire surface of the cell may be regulated by flow.
Expression of PECAM-1 Is Not Related to Lipids or Flow
PECAM-1 has been reported to be constitutively expressed on the
endothelium of all vessels, including the aorta,
arteries, capillaries, and veins.34 In the
present study, PECAM-1 was equally distributed over the entire
surface of the aorta, including advanced lesions. There are no apparent
differences in staining intensity between lesion-prone and other sites,
ApoE -/- and control mice, or younger and older mice, which suggest
that PECAM-1 is not regulated by rheological forces, lipid levels, or
age. Davies et al34 observed that all of the ECs
expressed PECAM-1 equally throughout the artery, including
endothelium over plaques, in human coronary
arteries.
PECAM-1 is primarily localized at intercellular junctions.40 Although the en face methods in the present study do not permit detection of PECAM-1 at these sites, microscopic examination did reveal the localization of PECAM-1 on the surface adjacent to the cell periphery. The distribution at the cell periphery and intercellular junctions may help to explain how this molecule plays a role in transmigration of monocytes between the endothelial junctions.9 Because a small amount (15%) of PECAM-1 is exposed at the apical surface and the bulk is located in the intercellular junction, Muller et al9 hypothesized that an apical-basal gradient acts as a haptotactic gradient produces directed migration of monocytes through the junction. Our photomicrographs also suggest that such a gradient of PECAM-1 exists from the center to the periphery of the cell. Such a pattern could help to attract monocytes to the borders of the cells. Thus, PECAM-1 could participate with ICAM-1 and VCAM-1 in the process of lesion initiation.9 18
Can the Localization and Repertoire of Adhesion Molecule Expression
in the ApoE -/- Mouse Explain Leukocyte Infiltration in
Atherosclerotic Lesions?
Studies of human atherosclerosis suggest that
lesion formation represents an inflammatory-fibroproliferative
response to altered lipoprotein metabolism, particularly in
vascular regions exposed to hemodynamic
strain.41 42 43 44 Monocyte and T-cell infiltration
and activation are typical components of human atherosclerotic lesions,
which are also observed in lesions of ApoE -/-
mice.13 45 46 The presence of abundant CD4+ T
lymphocytes in ApoE -/- mice and their expression of CD25, which is
indicative of recent activation, suggest that immune activation is part
of lesion formation.46 These authors also found
abundant class II major histocompatibility complex expression on
macrophages, which suggests release of cytokines from
activated T cells. Thus, the immunophenotype of the
murine ApoE -/ lesions closely resembles that of human lesions.
We have qualitatively characterized a distinct pattern of adhesion molecule expression in the ApoE -/- mice at lesion-prone sites. PECAM-1 is diffusely localized throughout the aorta, but it is particularly concentrated at the cell periphery. Of the molecules we studied, only VCAM-1 appeared to be induced in response to hypercholesterolemia and its associated changes, including increased levels of oxidized lipoproteins. In contrast, the relative expression of ICAM-1 was not altered by the presence or absence of hypercholesterolemia at lesion-prone sites. ICAM-1 was primarily localized over the surface of ECs and was prominent on microvilli. Although our analysis was limited to these three adhesion molecules, their specificity and pattern of expression may account for a significant proportion of the lymphocyte and monocyte recruitment observed in ApoE -/- lesions. VCAM-1 expression precedes leukocyte accumulation, can initiate both monocyte and lymphocyte tethering and rolling, and can induce firm adhesion in the absence of chemoattractants. At lesion-prone sites, ICAM-1 localization on microvilli will enhance firm adhesion for leukocytes in the primary, transient adhesion step, and increased expression of ICAM-1 over the surface of the endothelium will promote cell arrest where cell-cell contact has already been established. Finally, transendothelial cell migration, which leads to subendothelial deposition of the leukocytes and formation of early fatty streaks, is supported by universally expressed PECAM-1 as well as possibly enhanced by locally expressed VCAM-1.
Our studies suggest that VCAM-1 and ICAM-1 may coordinately define the lesion-prone sites. In particular, what impact would blockade of VCAM-1 have on the formation of lesions of atherosclerosis? Analysis of VCAM-1–deficient mice has been difficult because few of the homozygous-deficient mice are viable.47 Phenotypic analysis suggests that VCAM-1 is required for development of the extraembryonic circulatory system and embryonic heart.47 48 However, in future studies it will be important to analyze the impact of VCAM-1 inhibition, as our data strongly support a role for VCAM-1 in both the initiation and progression of lesions of atherosclerosis.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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The research was supported in part by National Institutes of Health (Bethesda, Md) grant HL18645 to R.R. and E.W.R., an unrestricted grant for cardiovascular research from Bristol-Myers Squibb Company to R.R., and grant-in-aid No. 07457051 for scientific research from the Ministry of Education, Science, Sports, and Culture of Japan to Y.N. The authors gratefully acknowledge Dr Renée Le Boeuf for providing mice; Dr Volkhard Lindner for helpful discussions; Dr Annemarie Walsh for arranging shipment of mice, Roderick Browne and Stephanie Lara for expert technical assistance, Kris Carroll for preparation of figures and Barbara Droker for editorial assistance. We also thank members of Russell Ross's laboratory for helpful discussions and assistance during the course of this work.
Received October 10, 1997; accepted January 7, 1998.
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References |
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D. Seo, T. Wang, H. Dressman, E. E. Herderick, E. S. Iversen, C. Dong, K. Vata, C. A. Milano, F. Rigat, J. Pittman, et al. Gene Expression Phenotypes of Atherosclerosis Arterioscler. Thromb. Vasc. Biol., October 1, 2004; 24(10): 1922 - 1927. [Abstract] [Full Text] [PDF]
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S. Dunzendorfer, H.-K. Lee, and P. S. Tobias Flow-Dependent Regulation of Endothelial Toll-Like Receptor 2 Expression Through Inhibition of SP1 Activity Circ. Res., October 1, 2004; 95(7): 684 - 691. [Abstract] [Full Text] [PDF]
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P. G. Frank, H. Lee, D. S. Park, N. N. Tandon, P. E. Scherer, and M. P. Lisanti Genetic Ablation of Caveolin-1 Confers Protection Against Atherosclerosis Arterioscler. Thromb. Vasc. Biol., January 1, 2004; 24(1): 98 - 105. [Abstract] [Full Text] [PDF]
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P. A. VanderLaan, C. A. Reardon, and G. S. Getz Site Specificity of Atherosclerosis: Site-Selective Responses to Atherosclerotic Modulators Arterioscler. Thromb. Vasc. Biol., January 1, 2004; 24(1): 12 - 22. [Abstract] [Full Text] [PDF]
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A. M. Troen, E. Lutgens, D. E. Smith, I. H. Rosenberg, and J. Selhub The atherogenic effect of excess methionine intake PNAS, December 9, 2003; 100(25): 15089 - 15094. [Abstract] [Full Text] [PDF]
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K. Schafer, K. Muller, A. Hecke, E. Mounier, J. Goebel, D. J. Loskutoff, and S. Konstantinides Enhanced Thrombosis in Atherosclerosis-Prone Mice Is Associated With Increased Arterial Expression of Plasminogen Activator Inhibitor-1 Arterioscler. Thromb. Vasc. Biol., November 1, 2003; 23(11): 2097 - 2103. [Abstract] [Full Text] [PDF]
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 N. Kobayashi, S.-i. Mita, K. Yoshida, T. Honda, T. Kobayashi, K. Hara, S. Nakano, Y. Tsubokou, and H. Matsuoka Celiprolol Activates eNOS Through the PI3K-Akt Pathway and Inhibits VCAM-1 Via NF-{kappa}B Induced by Oxidative Stress Hypertension, November 1, 2003; 42(5): 1004 - 1013. [Abstract] [Full Text] [PDF]
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E. L. Schiffrin and R. M. Touyz Multiple actions of angiotensin II in hypertension: benefits of AT1 receptor blockade J. Am. Coll. Cardiol., September 3, 2003; 42(5): 911 - 913. [Full Text] [PDF]
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G. E.R. Weller, E. Lu, M. M. Csikari, A. L. Klibanov, D. Fischer, W. R. Wagner, and F. S. Villanueva Ultrasound Imaging of Acute Cardiac Transplant Rejection With Microbubbles Targeted to Intercellular Adhesion Molecule-1 Circulation, July 15, 2003; 108(2): 218 - 224. [Abstract] [Full Text] [PDF]
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K. H. Han, Y. Chen, M. K. Chang, Y. C. Han, J.-H. Park, S. R. Green, A. Boullier, and O. Quehenberger LDL activates signaling pathways leading to an increase in cytosolic free calcium and stimulation of CD11b expression in monocytes J. Lipid Res., July 1, 2003; 44(7): 1332 - 1340. [Abstract] [Full Text] [PDF]
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H. D. Lieu, S. K. Withycombe, Q. Walker, J. X. Rong, R. L. Walzem, J. S. Wong, R. L. Hamilton, E. A. Fisher, and S. G. Young Eliminating Atherogenesis in Mice by Switching Off Hepatic Lipoprotein Secretion Circulation, March 11, 2003; 107(9): 1315 - 1321. [Abstract] [Full Text] [PDF]
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 J. H. Von der Thusen, J. Kuiper, T. J. C. Van Berkel, and E. A. L. Biessen Interleukins in Atherosclerosis: Molecular Pathways and Therapeutic Potential Pharmacol. Rev., March 1, 2003; 55(1): 133 - 166. [Abstract] [Full Text] [PDF]
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N. van Royen, I. Hoefer, M. Bottinger, J. Hua, S. Grundmann, M. Voskuil, C. Bode, W. Schaper, I. Buschmann, and J.J. Piek Local Monocyte Chemoattractant Protein-1 Therapy Increases Collateral Artery Formation in Apolipoprotein E-Deficient Mice but Induces Systemic Monocytic CD11b Expression, Neointimal Formation, and Plaque Progression Circ. Res., February 7, 2003; 92(2): 218 - 225. [Abstract] [Full Text] [PDF]
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D. M. Tham, B. Martin-McNulty, Y.-X. Wang, V. Da Cunha, D. W. Wilson, C. N. Athanassious, A. F. Powers, M. E. Sullivan, and J. C. Rutledge Angiotensin II injures the arterial wall causing increased aortic stiffening in apolipoprotein E-deficient mice Am J Physiol Regulatory Integrative Comp Physiol, December 1, 2002; 283(6): R1442 - R1449. [Abstract] [Full Text] [PDF]
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J. Middleton, A. M. Patterson, L. Gardner, C. Schmutz, and B. A. Ashton Leukocyte extravasation: chemokine transport and presentation by the endothelium Blood, December 1, 2002; 100(12): 3853 - 3860. [Abstract] [Full Text] [PDF]
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Y. Okamoto, S. Kihara, N. Ouchi, M. Nishida, Y. Arita, M. Kumada, K. Ohashi, N. Sakai, I. Shimomura, H. Kobayashi, et al. Adiponectin Reduces Atherosclerosis in Apolipoprotein E-Deficient Mice Circulation, November 26, 2002; 106(22): 2767 - 2770. [Abstract] [Full Text] [PDF]
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G. Wang, C. W.H. Woo, F. L. Sung, Y. L. Siow, and K. O Increased Monocyte Adhesion to Aortic Endothelium in Rats With Hyperhomocysteinemia: Role of Chemokine and Adhesion Molecules Arterioscler. Thromb. Vasc. Biol., November 1, 2002; 22(11): 1777 - 1783. [Abstract] [Full Text] [PDF]
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R. P. Choudhury, V. Fuster, J. J. Badimon, E. A. Fisher, and Z. A. Fayad MRI and Characterization of Atherosclerotic Plaque: Emerging Applications and Molecular Imaging Arterioscler. Thromb. Vasc. Biol., July 1, 2002; 22(7): 1065 - 1074. [Abstract] [Full Text] [PDF]
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I. M. van der Meer, M. P.M. de Maat, M. L. Bots, M. M.B. Breteler, J. Meijer, A. J. Kiliaan, A. Hofman, and J. C.M. Witteman Inflammatory Mediators and Cell Adhesion Molecules as Indicators of Severity of Atherosclerosis: The Rotterdam Study Arterioscler. Thromb. Vasc. Biol., May 1, 2002; 22(5): 838 - 842. [Abstract] [Full Text] [PDF]
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L. Calabresi, M. Gomaraschi, B. Villa, L. Omoboni, C. Dmitrieff, and G. Franceschini Elevated Soluble Cellular Adhesion Molecules in Subjects With Low HDL-Cholesterol Arterioscler. Thromb. Vasc. Biol., April 1, 2002; 22(4): 656 - 661. [Abstract] [Full Text] [PDF]
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M. E. Rosenfeld Leukocyte Recruitment Into Developing Atherosclerotic Lesions: The Complex Interaction Between Multiple Molecules Keeps Getting More Complex Arterioscler. Thromb. Vasc. Biol., March 1, 2002; 22(3): 361 - 363. [Full Text] [PDF]
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R. J. Aiello, P.-A. Bourassa, S. Lindsey, W. Weng, A. Freeman, and H. J. Showell Leukotriene B4 Receptor Antagonism Reduces Monocytic Foam Cells in Mice Arterioscler. Thromb. Vasc. Biol., March 1, 2002; 22(3): 443 - 449. [Abstract] [Full Text] [PDF]
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T. Minami and W. C. Aird Thrombin Stimulation of the Vascular Cell Adhesion Molecule-1 Promoter in Endothelial Cells Is Mediated by Tandem Nuclear Factor-kappa B and GATA Motifs J. Biol. Chem., December 7, 2001; 276(50): 47632 - 47641. [Abstract] [Full Text] [PDF]
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G. K. Hansson Immune Mechanisms in Atherosclerosis Arterioscler. Thromb. Vasc. Biol., December 1, 2001; 21(12): 1876 - 1890. [Abstract] [Full Text] [PDF]
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A. K. Stannard, D. R. Riddell, S. M. Sacre, A. D. Tagalakis, C. Langer, A. von Eckardstein, P. Cullen, T. Athanasopoulos, G. Dickson, and J. S. Owen Cell-derived Apolipoprotein E (ApoE) Particles Inhibit Vascular Cell Adhesion Molecule-1 (VCAM-1) Expression in Human Endothelial Cells J. Biol. Chem., November 30, 2001; 276(49): 46011 - 46016. [Abstract] [Full Text] [PDF]
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 W.-J. ZHANG and B. FREI {alpha}-Lipoic acid inhibits TNF-{alpha}-induced NF-{kappa}B activation and adhesion molecule expression in human aortic endothelial cells FASEB J, November 1, 2001; 15(13): 2423 - 2432. [Abstract] [Full Text] [PDF]
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C. G. Kevil, R. P. Patel, and D. C. Bullard Essential role of ICAM-1 in mediating monocyte adhesion to aortic endothelial cells Am J Physiol Cell Physiol, November 1, 2001; 281(5): C1442 - C1447. [Abstract] [Full Text] [PDF]
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H. M. Dansky, C. B. Barlow, C. Lominska, J. L. Sikes, C. Kao, J. Weinsaft, M. I. Cybulsky, and J. D. Smith Adhesion of Monocytes to Arterial Endothelium and Initiation of Atherosclerosis Are Critically Dependent on Vascular Cell Adhesion Molecule-1 Gene Dosage Arterioscler. Thromb. Vasc. Biol., October 1, 2001; 21(10): 1662 - 1667. [Abstract] [Full Text] [PDF]
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D. M. Wuttge, P. Eriksson, A. Sirsjo, G. K. Hansson, and S. Stemme Expression of Interleukin-15 in Mouse and Human Atherosclerotic Lesions Am. J. Pathol., August 1, 2001; 159(2): 417 - 423. [Abstract] [Full Text]
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M. Yoshida, T. Sawada, H. Ishii, R. E. Gerszten, A. Rosenzweig, M. A. Gimbrone Jr, Y. Yasukochi, and F. Numano HMG-CoA Reductase Inhibitor Modulates Monocyte-Endothelial Cell Interaction Under Physiological Flow Conditions In Vitro : Involvement of Rho GTPase-Dependent Mechanism Arterioscler. Thromb. Vasc. Biol., July 1, 2001; 21(7): 1165 - 1171. [Abstract] [Full Text] [PDF]
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M. Umetani, C. Mataki, N. Minegishi, M. Yamamoto, T. Hamakubo, and T. Kodama Function of GATA Transcription Factors in Induction of Endothelial Vascular Cell Adhesion Molecule-1 by Tumor Necrosis Factor-{{alpha}} Arterioscler. Thromb. Vasc. Biol., June 1, 2001; 21(6): 917 - 922. [Abstract] [Full Text] [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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E. E. ERIKSSON, X. XIE, J. WERR, P. THOREN, and L. LINDBOM Direct viewing of atherosclerosis in vivo: plaque invasion by leukocytes is initiated by the endothelial selectins FASEB J, May 1, 2001; 15(7): 1149 - 1157. [Abstract] [Full Text] [PDF]
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D. Manka, R. G. Collins, K. Ley, A. L. Beaudet, and I. J. Sarembock Absence of P-Selectin, but Not Intercellular Adhesion Molecule-1, Attenuates Neointimal Growth After Arterial Injury in Apolipoprotein E-Deficient Mice Circulation, February 20, 2001; 103(7): 1000 - 1005. [Abstract] [Full Text] [PDF]
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G. W. Cockerill, T. Y. Huehns, A. Weerasinghe, C. Stocker, P. G. Lerch, N. E. Miller, and D. O. Haskard Elevation of Plasma High-Density Lipoprotein Concentration Reduces Interleukin-1-Induced Expression of E-Selectin in an In Vivo Model of Acute Inflammation Circulation, January 2, 2001; 103(1): 108 - 112. [Abstract] [Full Text] [PDF]
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M.-C. Bourdillon, R. N. Poston, C. Covacho, E. Chignier, G. Bricca, and J. L. McGregor ICAM-1 Deficiency Reduces Atherosclerotic Lesions in Double-Knockout Mice (ApoE-/-/ICAM-1-/-) Fed a Fat or a Chow Diet Arterioscler. Thromb. Vasc. Biol., December 1, 2000; 20(12): 2630 - 2635. [Abstract] [Full Text] [PDF]
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K. Zibara, E. Chignier, C. Covacho, R. Poston, G. Canard, P. Hardy, and J. McGregor Modulation of Expression of Endothelial Intercellular Adhesion Molecule-1, Platelet-Endothelial Cell Adhesion Molecule-1, and Vascular Cell Adhesion Molecule-1 in Aortic Arch Lesions of Apolipoprotein E-Deficient Compared With Wild-Type Mice Arterioscler. Thromb. Vasc. Biol., October 1, 2000; 20(10): 2288 - 2296. [Abstract] [Full Text] [PDF]
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J. A. de Lemos, C. H. Hennekens, and P. M. Ridker Plasma concentration of soluble vascular cell adhesion molecule-1 and subsequent cardiovascular risk J. Am. Coll. Cardiol., August 1, 2000; 36(2): 423 - 426. [Abstract] [Full Text] [PDF]
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F. E. Thorngate, L. L. Rudel, R. L. Walzem, and D. L. Williams Low Levels of Extrahepatic Nonmacrophage ApoE Inhibit Atherosclerosis Without Correcting Hypercholesterolemia in ApoE-Deficient Mice Arterioscler. Thromb. Vasc. Biol., August 1, 2000; 20(8): 1939 - 1945. [Abstract] [Full Text] [PDF]
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Y. Huo, A. Hafezi-Moghadam, and K. Ley Role of Vascular Cell Adhesion Molecule-1 and Fibronectin Connecting Segment-1 in Monocyte Rolling and Adhesion on Early Atherosclerotic Lesions Circ. Res., July 21, 2000; 87(2): 153 - 159. [Abstract] [Full Text] [PDF]
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S. Oguchi, P. Dimayuga, J. Zhu, K.-Y. Chyu, J. Yano, P. K. Shah, J. Nilsson, and B. Cercek Monoclonal Antibody Against Vascular Cell Adhesion Molecule-1 Inhibits Neointimal Formation After Periadventitial Carotid Artery Injury in Genetically Hypercholesterolemic Mice Arterioscler. Thromb. Vasc. Biol., July 1, 2000; 20(7): 1729 - 1736. [Abstract] [Full Text] [PDF]
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W. Shi, N. J. Wang, D. M. Shih, V. Z. Sun, X. Wang, and A. J. Lusis Determinants of Atherosclerosis Susceptibility in the C3H and C57BL/6 Mouse Model : Evidence for Involvement of Endothelial Cells but Not Blood Cells or Cholesterol Metabolism Circ. Res., May 26, 2000; 86(10): 1078 - 1084. [Abstract] [Full Text] [PDF]
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Z. M. Dong, A. A. Brown, and D. D. Wagner Prominent Role of P-Selectin in the Development of Advanced Atherosclerosis in ApoE-Deficient Mice Circulation, May 16, 2000; 101(19): 2290 - 2295. [Abstract] [Full Text] [PDF]
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