review
An integrated approach for the mechanisms
responsible for atherosclerotic plaque regression
Andrew A Francis BSc, Grant N Pierce PhD FACC FAHA FISHR FIACS FCAHS FRSM FAPS
AA Francis, GN Pierce. An integrated approach for the mechanisms
responsible for atherosclerotic plaque regression. Exp Clin Cardiol
2011;16(3):77-86.
Atherosclerosis was originally considered to be an ongoing process that was
inevitably associated with age. However, plaques are highly dynamic, and
are able to progress, stabilize or regress depending on their surrounding
milieu. A great deal of research attention has been focused on understand-
ing the involvement of high-density lipoprotein in atherosclerotic plaque
regression. However, atherosclerotic plaque regression encompasses a vari-
ety of processes that can be grouped into three main areas: removal of lipids
and necrotic material; restoration of endothelial function and repair of
denuded areas; and cessation of vascular smooth muscle cell proliferation
and phenotype reversal. In addition to the role of high-density lipoproteins
A therosclerosis emerged as a major health dilemma during the
early 20th century. Nearly a full century later, atherosclerosis has
become the leading cause of death worldwide (1,2). It is now under-
stood that atherosclerotic lesions are produced from a complex array of
molecular and cellular events that act in concert to form asymmetric
focal thickenings of the arterial tunica intima (3,4).
Atherosclerosis is initiated by the response of endothelial cells (ECs)
to injury caused by myriad noxious stimuli including hyperglycemia,
hypertension, hyperlipidemia, infectious agents, obesity, modified lipo-
proteins, homocysteine, nicotine, free radicals, altered changes in arter-
ial blood flow shear stress and normal spontaneous metabolic damage
(5-10). This initial damage induces a loss of basal endothelial homeosta-
sis causing endothelial dysfunction (11). The resulting increase in endo-
thelial permeability permits the accumulation of low-density lipoprotein
(LDL) and cellular debris within the tunica intima of the vessel wall,
eventually leading to endothelial activation. Once activated, ECs pro-
duce an array of chemoattractant cytokines such as monocyte
chemoattractant protein-1, macrophage colony-stimulating factor,
interferon-g, platelet-endothelial cell adhesion molecule-1, interleukin
(IL)-1, IL-6 and tumour necrosis factor-a (TNF-a), creating a pro-
inflammatory environment that attracts circulating monocytes and
T lymphocytes (12-14). Normally, ECs do not express molecules that
facilitate the adhesion of circulating leukocytes. However, activated ECs
express vascular cell adhesion molecules such as intercellular adhesion
molecules (ICAMs), E-selectin and P-selectin, which mediate leukocyte
adhesion and infiltration (12,13). Endothelial-derived cytokines subse-
quently drive the differentiation of monocytes into macrophages, which
use pattern recognition receptors to sequester LDL, modified LDL, free
cholesterol (FC) and cholesteryl esters (3). Together, activated leuko-
cytes and ECs continue to produce proinflammatory cytokines and
growth factors that promote the transition of smooth muscle cells from
a quiescent, contractile phenotype to an active and proliferative syn-
thetic phenotype that deposits extracellular matrix at the site of injury,
forming a fibrous cap (15-18). Continued exposure to various noxious
stimuli, in conjunction with a proinflammatory environment, further
exacerbates plaque severity, perpetuates plaque progression, and
Institute of Cardiovascular Sciences, St Boniface Hospital Research Centre, Department of Physiology, Faculties of Medicine and Pharmacy, University of
Manitoba, Winnipeg, Manitoba
Correspondence: Dr Grant N Pierce, Institute of Cardiovascular Sciences, St Boniface Hospital Research Centre, 351 Tache Avenue, Winnipeg,
Manitoba R2H 2A6. Telephone 204-235-3206, fax 204-235-0793, e-mail gpierce@sbrc.ca
Received for publication July 25, 2011. Accepted July 27, 2011
Exp Clin Cardiol Vol 16 No 3 2011
in lipid removal, resident macrophages and foam cells are able to regain
motility and rapidly migrate on milieu improvement, moving both lipids
and necrotic material to regional lymph nodes. Neighbouring endothelial
cells can proliferate and replace dead and dysfunctional cells. Circulating
endothelial progenitor cells can similarly restore vessel function. Finally,
abrogation of smooth muscle cell proliferation occurs secondarily to these
processes. This information is integrated in the current article to present a
comprehensive and clear depiction of plaque regression. This integrated
view of regression is essential to optimize the pharmaceutical targeting of
the many processes and pathways involved in plaque regression.
Key Words: Atherosclerosis; Endothelium; Macrophage migration; Regression;
Reverse cholesterol transport; Smooth muscle cells
promotes plaque destabilization, resulting in plaque rupture which mani-
fest as acute events such as stroke or myocardial infarction (19,20).
During the past few decades, an improved understanding of athero-
sclerotic pathophysiology has enabled researchers to consider the pos-
sibility of inducing plaque regression in addition to the more
conventional therapeutic goal of reducing plaque progression.
Traditionally, atherosclerosis was viewed as an inevitable unidirec-
tional process that begins in childhood and manifests during adult-
hood (20). However, during the 1980s, Badimon et al (21) showed
that plaque development is not simply a permanent process associated
with age, but rather a dynamic process that can be slowed, stopped or
reversed. In spite of the evidence supporting the existence of plaque
regression, the concept of ‘plaque regression’ was resisted for decades.
Critics of regression asserted that the physical attributes of an athero-
sclerotic plaque, including calcification, necrosis and fibrosis, indi-
cated stability, and the molecular processes associated with plaques
such as oxidative damage, cell proliferation and transformation seemed
to imply that regression would be very difficult or impossible to
achieve. Furthermore, at that time, a majority of animal studies
attempting to induce regression in advanced plaques had failed (22-26).
However, the ability of even advanced lesions to regress on robust
reductions in LDL levels and increases in high-density lipoprotein
(HDLs) levels has established plaque regression as a well-accepted
process (27,28). Atherosclerosis is now known as a highly dynamic
process in which plaques are able to either progress or regress,
depending on the surrounding milieu (29,30). However, despite the
plethora of research, a comprehensive discussion that incorporates and
integrates the current knowledge of the various processes known to
occur during plaque regression remains to be completed.
What is atherosclerotic plaque regression? Ideally, plaque regres-
sion would be the return of the arterial wall to its initial state.
However, with the exception of fatty streaks, even under ideal condi-
tions, the complete reversal of plaque formation does not occur (30). It
is important to understand that plaque regression is not simply plaque
progression in reverse. Rather, the mechanisms of plaque regression are
distinct and are composed of three important processes: the reduction
©2011 Pulsus Group Inc. All rights reserved 77
Francis and Pierce

Figure 1) The integrated mechanism of atherosclerotic plaque regression. The mechanism of regression is complex and involves lipoproteins, endothelial progeni-
tor cells (EPCs), macrophages and vascular smooth muscle cell (SMC). The transport of cholesterol back to the liver begins with the synthesis and secretion of
lipid-poor apolipoprotein (apo) AI by the liver and intestine. The first step of reverse cholesterol transport (RCT) is initiated by the ATP-binding cassette trans-
porter (ABCA) A1-mediated efflux of cholesterol from peripheral cells to apoAI or preb-high-density lipoprotein (HDL). Preb-HDL matures to HDL3 after
lecithin:cholesterol acyltransferase (LCAT) esterifies its cholesterol producing cholesterol ester. Cholesteryl ester transferase (CEPT) can further mature HDL3
into HDL2 through the transfer of its cholesterol esters to apoB-containing lipoproteins (low-density lipoprotein [LDL], very low LDL [VLDL] and intermediate-
density lipoprotein [IDL]). Mature HDL particles may then be cleared from the circulation by the liver or intestine via the scavenger receptor class B1 (SR-B1)
receptor, which mediates holoparticle uptake. Lipases can release apoAI from HDL, which are filtered and degraded by the kidneys. HDL can also unload
cholesterol into the liver or intestine after it has acquired apoE, which enables HDL to interact with the LDL receptor. Finally, ABCA1 located on enterocytes
causes the unloading of cholesterol from HDL particles. To complete reverse cholesterol transport, cholesterol is secreted into bile by the liver or secreted directly
into the intestinal lumen by the apical member transporters scavenger receptor class B type 1 (SR-B1), ABCG5 and ABCG8. Both the intestine and liver
remove cholesterol from the body as feces. During regression, damaged, denuded areas of the vessels’ endothelial lining or damaged endothelial cells can be
replaced by circulating bone marrow derived EPCs. Additionally, the amelioration of the pathological components of the plaque will abrogate vascular SMC
migration and proliferation, and induces migration of macrophages away from the plaque. HDL production, maturation and degradation are indicated by black
arrows and lines. Removal of cholesterol from peripheral tissue is indicated by red arrows and lines. Clearance of cholesterol within circulation is indicated by
blue arrows and lines. Movement of EPCs is indicated by purple arrows and lines. oxLDL Oxidized LDL

or clearance of necrotic and extracellular material from the tunica
intima; endothelial repair, regeneration and return to homeostasis; and
the cessation of smooth muscle cell proliferation (Figure 1). Although
a reduction of luminal area, plaque volume or intimal medial thickness
are indexes commonly used in diagnostic medicine to assess plaque
regression, and are possible estimations of regression, they are cur-
rently unable to capture the true complexity of this process.
REmovAl oF ExtRACEllulAR ANd
iNtRACEllulAR liPids ANd NECRotiC
mAtERiAl
Although the mechanisms of regression are beginning to be under-
stood, there has been considerable progress in isolating the important
players in regression and understanding their biological role. Attention,
however, within the past few decades has been focused on reverse
cholesterol transport (RCT) and its major player, HDL.
Hdl and its influence on atherosclerotic plaque regression
though RCt
Hdl classification: Since the early 1970s, HDL cholesterol (HDL-C)
has been associated with a decrease in cardiovascular disease (CVD)
(31). Gordon et al (32) demonstrated that there is an inverse relation-
ship between systemic levels of HDL-C and the prospective risk for
coronary artery disease; this correlation was maintained even at very
low levels of LDL cholesterol. Animal and human studies have shown
that infusions of synthetic HDL particles can induce regression of
atherosclerotic plaque (21,33,34). Moreover, increases in HDL-C by
even 1 mg/dL are associated with a 3% to 4% decrease in cardiovascu-
lar-related mortality (35). Since the discovery of the inverse relation-
ship of HDL-C with CVD, a large amount of information has been
obtained about its structure and function. Although the full mechan-
ism of HDL’s anti-atherosclerotic effects are not well known, it is
becoming clear that HDL participates in ameliorating nearly all

78 Exp Clin Cardiol Vol 16 No 3 2011


Table 1
High-density lipoprotein (HDl) characteristics
HDl particle Density, g/ml Preferred efflux pathway
Preβ-HDL 1.21 ABCA1
Aqueous diffusion
HDL2 1.063–1.125 SR-BI
ABCGI
Aqueous diffusion
HDL3 1.125–1.21 SR-BI
ABCGI
Aqueous diffusion
ABC ATP-binding cassette transporter; SR-BI Scavenger receptor class B type I
aspects of plaque pathogenicity by restoring endothelial cell basal
function, decreasing smooth muscle cell proliferation and migration,
and decreasing intraplaque inflammation and cellular debris retention
(36). It has also become clear that not only is the concentration of
HDL within the circulation important for its anti-inflammatory effect,
but also its quality (37). Nevertheless, what has been well established
is HDL’s contribution to atherosclerotic plaque regression by promot-
ing RCT. However, to understand the RCT pathway, it is essential to
become aware of the various structures of HDL.
HDLs were first discovered by Gofman et al (38) in experimental stud-
ies using analytical ultracentrifugation to separate and categorize distinct
serum lipoprotein families according to their hydrated density. HDLs were
defined as lipoproteins of small diameter (5 nm to 17 nm) that sediment
in the density region (1.063 g/mL to 1.21 g/mL) (Table 1). It is now
understood that HDL is a highly heterogeneous group of particles, and
composed of many subclasses. The difference between HDL subclasses
is ultimately dependent on the particles’ physical properties includ-
ing shape, size, density and charge; however, these subclasses can be
reclassified according to differences in lipid transfer proteins, enzymes,
lipid content and apolipoproteins (39,40). Many methods have been
developed to separate HDL into its various subclasses. Gofman et al
(38) developed an analytical ultracentrifugation method for identify-
ing the distinct subclasses of HDL particles, which is currently the gold
standard technique for HDL subclass determination (41,42). Using
this technique and other ultracentrifugation methods, such as rate-
zonal or single vertical spin ultracentrifugation, HDLs can be separated
into two main subfractions based on their respective densities: HDL2
(1.063 g/mL to 1.125 g/mL) and HDL3 (>1.125 g/mL to 1.21 g/mL)
(43-45). These two HDL subfractions can also be further subdivided
based on their size (diameter) using nondenaturing polyacrylamide gel
electrophoresis, yielding HDL2b (9.7 nm to 12.0 nm), HDL2a (8.8 nm
to 9.7 nm), HDL3a (8.2 nm to 8.8 nm), HDL3b (7.8 nm to 8.2 nm)
and HDL3c (7.2 nm to 7.8 nm) (46). Another classification system of
HDL arose with the use of agarose gel electrophoresis, separating HDL
based on relative negative surface charge density. a-HDL, which com-
prises the majority of plasma HDL, has a high negative charge density
compared with preb-HDL, also known as nascent HDL (47-49). Two-
dimensional electrophoresis, which combines both agarose gel and
gradient gel electrophoresis, can further resolve a-HDL and preb-HDL
into 12 distinct HDL subclasses based on their size and motilities with
respect to albumin: preb (preb1, preb2 and preb3), a (a1, a2 and
a3) and prea (prea1, prea2 and prea3) (48,50). Finally, HDL can be
classified by immunoaffinity methods according to its apolipoprotein
(apo) A composition. The majority of proteins found in HDL are
either apoAI (65% to 70%) and apoAII (20% to 25%). Furthermore,
two major apoA-containing HDL subclasses exist: HDL particles may
contain both apoAI and apoAII in a 2:1 molar ratio, or they can
contain only apoAI (50,51). Adding to HDL’s complexity, several
proteins have been shown to circulate in the plasma bound to HDL
including apoA-IV, apoC, apoE, apoF, lecithin:cholesterol acyltrans-
ferase, cholesteryl ester transferase (CETP), phospholipid transferase
Exp Clin Cardiol Vol 16 No 3 2011
Mechanisms of plaque regression
electrophoretic mobility Subpopulations Diameter, nm
Preβ Preβ1 5.4–7
Preβ2 12–14
Preβ3
α HDL2b 9.7–12.0
HDL2a 8.8–9.7
α HDL3a 8.2–8.8
HDL3b 7.8–8.2
HDL3c 7.2–7.8
protein, paraoxonase and platelet-activating factor acetylhydrolase.
Moreover, proteomic analyses have shown that HDL may contain
more than 48 proteins. It is generally accepted that the majority
of plasma HDL is in the form of preb-HDL, as well as HDL2 and
HDL3 – the mature forms of HDL that are equivalent to a-HDL
(52,53) (Table 1). Despite the many different classifications of HDL,
all HDL particles have in common their ability to mediate the process
of RCT.
RCt: According to the generally accepted definition of RCT, the first
step of RCT is the efflux of extrahepatic cholesterol from intracellular
cholesterol pools. This usually focuses on the removal of cholesterol
from macrophages. Alternatively, critics of this view attest that assem-
bly of HDL particles and their subsequent secretion into the circula-
tion is the initial step of this process (54-56). In the present review,
however, the overview of HDL’s involvement in RCT will begin with
the production and release of HDL to provide a clear synopsis of RCT.
Despite the disagreement regarding the initial steps in RCT, it is
accepted that the acquisition of cholesterol from peripheral stores by
HDL is the major mechanism for promoting atherosclerotic plaque
regression.
The production of all HDL subclasses begins with the synthesis of
apoAI and apoAII. These proteins are primarily generated in the liver
and secondarily by the small intestine (56,57). Both hepatocytes and
enterocytes can secrete lipid-poor apoAI and AII into the circulation,
where it acquires phospholipids and cholesterol to form preb-HDL
(58-60). Regardless, the majority of apoA produced in the intestine
is packaged into chylomicrons, which are eventually internalized
by the liver. In contrast, hepatocyte apoA secretion into plasma is
more complex. Similar to chylomicrons, very low density lipoprotein
(VLDL) – another triglyceride-rich lipoprotein – can lose cholesterol.
Phospholipids can also lose or gain apolipoproteins during lipolysis,
which generates preb-HDL. VLDL can also be amalgamated into
HDL2 and HDL3 (61). Finally, hepatocytes can synthesize and secrete
both apoA and preb-HDL directly into the circulation. In spite of the
different modes of release, once in the circulation, preb-HDL can be
used for RCT.
The first and rate-limiting steps of RCT is cholesterol efflux from
macrophages, and the peripheral tissue to the HDL particle (62).
There are currently four proposed mechanisms of cholesterol efflux
into lipid-poor apoAI and the various HDL particles: aqueous diffu-
sion, scavenger receptor class B type 1 (SR-BI)-mediated efflux, ATP-
binding cassette (ABC) transporter A1-mediated efflux and
ABCG1-mediated efflux (54,55).
First, cholesterol efflux can occur passively by adhering to its con-
centration gradient. As a result, the passive diffusion pathway is
bidirectional, and the rate-limiting step of this process is dependent on
the ratios and interactions between the FC in the donor cells and the
phospholipids within the plasma membrane of the acceptor molecule –
the HDL particle (62,63). The kinetics of this interaction are acceler-
ated by higher proportions of unsaturated phospholipids and decreases
in the sphingomyelin content of the plasma membrane (64,65).
79
Francis and Pierce
Because cholesterol efflux by this pathway is not affected by HDL
particle size, all HDL subclasses are equal in their ability to accept
cholesterol through aqueous diffusion (66).
In contrast to aqueous diffusion, the remaining three cholesterol
efflux pathways are mediated by protein-protein interactions.
Cholesterol efflux can be mediated by the ATP-independent, passive
SR-BI pathway. Cholesterol transport is initiated by the binding of
HDL to SR-BI, which subsequently forms a hydrophobic channel
allowing efflux to occur (67). SR-BI promotes efflux exclusively to
larger, more mature HDL particles such as HDL2 and HDL3, which
can further increase the SR-BI-mediated selective uptake of choles-
terol if they contain apoAII (68). Because this process is bidirectional,
HDL may be a donor and an acceptor of cholesterol. Thus, its role in
aiding RCT in macrophages may not be as important as the remaining
energy-dependent cholesterol efflux pathways (69).
Cholesterol and phospholipid efflux to apoAI is promoted by the
interaction of ABCA1 with preb-HDL or with lipid-poor apoAI (49).
The activation of ABCA1 induces the removal of cholesterol from the
plasma membrane of the donor cell and can also cause efflux from
intracellular cholesterol pools (70,71). The rate of lipid efflux is
dependent on the concentration of activated ABCA1 and on the
amount of unsaturated phospholipids in the donor cell (72). In addi-
tion, the concentration of ABCA1 in the plasma membrane is regu-
lated by the interaction of apoA1 and ABCA1, which prevents its
intracellular degradation (73).
Another member of the ABC family of transporters, ABCG1, is
the last major efflux pathway in RCT. ABCG1, which is involved with
regulating intracellular cholesterol homeostasis, interacts with all sub-
classes of HDL (74-76). It also mediates cholesterol efflux through the
reorganization of existing cholesterol pools, and increasing its diffusion
to and uptake by HDL particles. Although all HDL subclasses can
mediate efflux through the ABCG1 pathway, larger HDL particles are
more effective acceptors, as in the SR-BI efflux pathway (77).
Following the removal of cholesterol from peripheral sites, HDL
undergoes further maturation characterized by increased particle size
due to the progressive accumulation of cholesterol (78). In circulation,
cholesterol becomes esterified to preb-HDL through an apoA1-
mediated reaction with lecithin:cholesterol acyltransferase, converting
lecithin and cholesterol into lysolecithin and CE (79). Because CE are
hydrophobic, they can move to the developing core of the HDL par-
ticle, which causes it to enlarge and become spherical. This ultimately
transforms preb-HDL into HDL3 or HDL2. This process not only
increases the surface area for FC acceptance, it also helps maintain the
FC gradient (69,80). Once a mature HDL particle is synthesized, it has
three possible fates. First, lipolytic enzymes such as lipoprotein, hep-
atic and endothelial lipases can hydrolyze triglycerides and phospho-
lipids causing apoAI to dissociate from HDL, which facilitates the
clearing of apoAI from circulation by the kidneys and the conversion
of mature HDL particles back into nascent preb-HDL (81-83).
Second, constituents of mature HDL particles may be transported to
other HDL subclasses or other lipoproteins. For example, certain
plasma lipid transfer proteins can transfer triacylglycerol and phospho-
lipids among lipoproteins (84). CETP transfers the majority of CEs to
apoB-containing lipoproteins, such as VLDL and LDL, which produ-
ces small cholesterol ester-depleted HDL particles that are either
cleared by the kidneys or incorporated into another HDL particle
forming a large mature HDL particle (85). ApoB-containing lipopro-
teins can be removed from the circulation by hepatic LDL receptors
and catabolized by the liver, and hepatic SR-BI can also bind LDL and
VLDL. Thus, the CETP pathway is believed to be an important route
of RCT (86-90). However, clinical studies involving humans with
CETP deficiencies report conflicting and controversial results, which
ultimately has led to questioning of whether CETP is detrimental or
instrumental in CVD (19,91-94). It is also likely that cholesterol
transferred to LDL or VLDL can be redeposited to peripheral tissue.
Third, cholesterol can be returned to the liver through the clearance
of HDL from the circulation. SR-BI, located on the surface of liver or
80
adrenal cells, recognizes circulating HDL particles and facilitates the
unloading of their FC and cholesterol esters (95). This process does
not involve the internalization and degradation of the HDL particle.
Thus, removal of cholesterol and CEs produces nascent HDL particles
that have the potential to be recycled back into the RCT pathway
(85). As opposed to HDL efflux from macrophages, SB-RI is the most
abundant receptor on hepatocytes, thus making this pathway an
important mode of cholesterol influx. An alternative method of influx
involves the acquisition of apoE enabling HDL to deliver cholesterol
to hepatic tissue through its interaction with LDL receptors, which
mediates the internalization of HDL particles and their subsequent
catabolism (96). Novel routes to HDL holoparticle uptake by hepato-
cytes, such as HDL internalization by the receptor P2Y13, continue to
be identified (97).
Cholesterol within hepatocytes must be secreted into the intestinal
lumen to complete the RCT pathway. The rate of cholesterol excre-
tion is dependent on several transporters on its apical membrane.
Cholesterol efflux into bile is dependent on both SR-BI and the ABC
family of transporters. The rate of cholesterol efflux is primarily con-
trolled by ABCG5 and ABCG8 transporters (98,99). Although SR-BI
can also facilitate cholesterol secretion into bile, it serves only a minor
role on the apical membrane, being secondary to the ABC transport-
ers. However, SR-BI is an important mode of influx on the basolateral
membrane of hepatocytes (100,101).
The hepatobiliary route of HDL-C removal is generally accepted to
be the major mode of cholesterol excretion. However, Cheng and
Stanley (102) suggested that there is an additional route to fecal chol-
esterol loss through a nonbiliary fecal route. Nonbiliary sterol loss is
believed to be regulated by the liver. Under conditions in which the
hepatic cholesterol load exceeds a manageable amount, cholesterol is
repackaged into plasma lipoproteins that are bound for secretion by
the intestines (103). Although the mechanism of the nonbiliary fecal
pathway is not well understood, many aspects are shared with the
hepatobiliary route of sterol loss. It has been suggested that lipopro-
teins responsible for the transport of cholesterol to the intestine are
either apoE-rich HDL or apoB-containing lipoproteins (104,105). It is
quite likely that most lipoproteins are able to facilitate this process
because enterocytes express SB-RI on their basolateral membrane
(78). Similar to hepatocytes, enterocytes express ABCG5/G8 as well
as SR-BI on their apical membranes, allowing the efflux of cholesterol
from the enterocyte to the intestinal lumen (106).
monocyte/macrophage migration
During regression, cholesterol removal is accompanied by the dis-
appearance of macrophage and foam cells. This is one of the first
noticeable indications of plaque regression (30). It was initially
believed that the disappearance of monocytes and macrophages from
atherosclerotic plaques was only caused by apoptosis, lysis in situ and
phagocytosis by new macrophages. However, it is now evident that
macrophages within atherosclerotic lesions can also regain motility
and migrate to regional lymph nodes when the local environment
improves.
mechanisms of cell motility and immobilization: Cells facilitate
migration through cell motility cycling. This process contains four
sequential events beginning with the following: polarization of the
cell; extension of lamellipodia at the leading edge; the formation of a
focal adhesion attaching the cell to the underlying substrate; and the
contraction and rear detachment of the cell resulting in cell move-
ment. The regulation of these events is coordinated by the Rho family
of GTPase (107). The exchange of GDP for GTP activates Rho-
GTPases, which control cytoskeleton remodelling by activating down-
stream targets (108). Two members of this family, RhoA – a GTPase
associated with actin filament organization and promotion of focal
adhesions – and Rac1 – which induces polymerization of actin that
forms both lamellipodia and membrane ruffles – have important roles
in cell immobilization (109,110).
Exp Clin Cardiol Vol 16 No 3 2011

During atherosclerosis, macrophages within atherosclerotic
plaques accumulate FC and CEs (111-113). Accumulation of choles-
terol causes apoptosis and secondary necrosis in macrophages and
impairs chemotaxis. This immobilization is associated with increased
levels of Rac-GTP, the active form of Rac, and reduced levels of
RhoA. The translocation of Rac to the plasma membrane facilitates
its activation. Cholesterol-rich domains within the inner leaflet of
the plasma membrane maintain Rac-GTP in the membrane. The loss
of proper cell polarization, cell spreading and plasma membrane ruf-
fling caused by increased Rac activity abrogates forward movement
of the cell (114-116).
mechanisms of macrophage migration during plaque regression: The
migration of macrophage and foam cells from atherosclerotic plaques
is complex and is controlled by plaque dynamics. Improvements in the
plaque milieu causes the transformation of macrophages from an
immobilized to a mobile state by the expression of dendritic cell mark-
ers (117,118) such as chemokine (C-C motif) receptor 7 (CCR7), an
essential requirement for dendrite cell migration (119). CCR7 control
of immune cell emigration is mediated by the activation and upregula-
tion of the liver X receptor (28). The downstream target of the liver X
receptor, ABCA1, is also unregulated (118). Macrophage/foam cell
migration and morphological transformation can be, in part, facili-
tated by ABCA1-induced cholesterol redistribution. ABCA1 may
decrease membrane cholesterol pools releasing Rac-GTP (120,121).
ABCG1 and LDL receptor-related protein 1 may also play a small role
in macrophage migration from atherosclerotic plaques (119,122).
ENdotHEliAl REPAiR, REGENERAtioN
ANd HomEostAsis
Vascular ECs serve as a dynamic barrier separating the vessel wall from
blood. They also control vascular homeostasis by regulating vascular
tone, leukocyte trafficking and vessel permeability. Endothelial dys-
function – an early hallmark of atherosclerosis – is characterized by the
conversion of ECs from a normal physiological phenotype to a vaso-
constrictive, procoagulant, platelet-activating phenotype that contrib-
utes to atherosclerosis (123,124). Prolonged endothelial dysfunction
can lead to cell apoptosis, which can ultimately denude the vessel wall
(125,126). To achieve atherosclerotic regression, these dysfunctional
ECs must be returned to basal homeostasis and dead cells need to be
replaced. Currently, there are three known mechanisms that can result
in endothelial cell replacement: circulating endothelial progenitor
cells, local endothelial cell proliferation and migration, and abroga-
tion of endothelial apoptosis.
Endothelial progenitor cells and vascular repair
The term ‘stem cell’ or ‘progenitor cell’ refers to immature cells that
have the ability to self-renew and differentiate into a variety of cell
types. Thus, these cells have the potential to restore the function of
damaged tissues (127,128). Endothelial progenitor cells (EPCs), simi-
lar to all progenitor cells, are lineage specific, and comprise a highly
heterogeneous population of cells capable of differentiating exclusively
into ECs (129). The majority of progenitor cells mature from hemato-
poietic stem cells. These stem cells are mainly isolated from bone mar-
row, peripheral blood and umbilical cord, but can be obtained from the
spleen, intestine, liver, adipose tissue and adventitia (130). Regardless
of their source, all hematopoietic stem cells are CD34+ and CD133+.
Hematopoietic stem cells can also produce nonerythroid myeloid and
granulocyte-macrophage lineages, as well as EPCs. Therefore, EPCs
are characterized by the co-expression of both hematopoietic stem cell
markers and endothelial markers such as vascular endothelial growth
factor receptor-2, CD31, endothelial nitric oxide (NO) synthase, and
vascular endothelial cadherin (130-134). Although hematopoietic
stem cells appear to be the main source of EPCs, other resident bone
marrow stem cells, such as mesenchymal stem cells, may generate
EPCs. In addition, CD14+ myeloid subsets express both the hemato-
poietic and endothelial markers, and CD14+ monocytic cells can dif-
ferentiate into ECs (135-138). EPCs are instrumental in maintaining
Exp Clin Cardiol Vol 16 No 3 2011
Mechanisms of plaque regression
the integrity of the vascular endothelium, which contribute to the
regression of atherosclerotic plaques.
To obtain any benefit from nontissue resident or exogenously
administered EPCs, they must be recruited by and migrate to the site of
injury. This process is orchestrated by resident cells of the injured area.
During atherosclerosis, various cell types within the plaque are capable
of mobilizing and homing EPCs to denudated vessels. First, EPCs are
released from their source upon stimulation from molecular signals
produced by immune cells within the plaque. Activated M2 type
macrophages promote vessel healing through the secretion of granulo-
cyte colony-stimulating factor (G-CSF) (139). G-CSF facilitates the
release of EPCs into circulation. In addition, cytokine-mediated release
of proteases such as elastase, cathepsin G and matrix metalloproteinase
(MMP)-9 discharges EPCs by cleaving the adhesive interaction
between EPCs and stromal cells (134,140). The released EPCs are sub-
sequently homed to and mobilized by the injured area. An important
homing signal is the chemokine stromal cell-derived factor-1 (SDF-1).
Under normal conditions, the bone marrow and many other tissues
constitutively express SDF-1. The bone marrow, however, produces a
gradient that favours the retention of EPCs. During conditions of
ischemia, inflammation and hypoxia, this gradient is reversed by the
expression of hypoxia-inducible factor-1, which upregulates SDF-1 in
injured tissues (141-144). In addition, NO, estrogen, HDL, vascular
endothelial growth factor and erythropoietin contribute to the increase
in the plasma titre of EPCs and their recruitment to the site of injury by
augmenting the phosphatidyl-inositol-3-phosphate (PIP3)/Akt path-
way (145-147). Once in the damaged area, cell adhesion molecules,
such as P/E-selectin and ICAM-1, mediate the binding of EPCs to the
injured endothelium (148). In severely damaged vessels, exposed
matrix proteins activate platelets that adhere to the denuded area.
Platelet activation causes microthrombi formation and the expression
of SDF-1, targeting EPCs to the damaged endothelium. Moreover,
EPCs potentially adhere not only to the endothelium, but also to plate-
lets by interacting with P-selectin and GPIIb integrin (149-151). After
EPC attachment, they differentiate into ECs under the influence of the
laminar shear stress of the blood (128,152).
Several studies have evaluated the beneficial effects of EPCs on
CVD. Bone marrow-derived EPCs can differentiate into ECs and
induce neovascularization in ischemic mouse tissue (153,154). There
is an inverse relationship between circulating (CD34+ and CD133+)
progenitor cells for both modifiable and nonmodifiable atherosclerotic
risk factors, such as smoking and age (155). Moreover, low circulating
levels of EPCs are found in patients who are at high risk of developing
coronary artery disease (156). Statin therapy, known to reduce the
incidence of CVD and cardiovascular events, was able to increase EPC
titre and engraftment efficiency (157,158). Physical exercise increases
NO and HDL production, both of which increase EPC recruitment
and EPC levels (159-161).
Despite the mounting evidence implicating progenitor cell involve-
ment in the regression of atherosclerosis, there are concerns and cau-
tion has been advised. Bone marrow-derived progenitor cells have
been associated with neovascularization and vessel remodelling, which
can cause plaque destabilization (130,162). In addition, EPCs that
have the osteoblast marker osteocalcin are retained within the lesion
for endothelial repair, but are also believed to lead to the induction
and progression of coronary calcification rather than normal endothel-
ial repair (163).
EC apoptosis, migration and proliferation
As atherosclerosis persists, ECs become apoptotic, leading to the
denudation of the vessel wall. Apoptosis is known to be initiated by
the activation of the death receptor and mitochondrial-mediated
apoptotic pathways. HDL may have a role in preventing EC apoptosis
and promoting endothelial repair (164). HDL can directly or indirectly
inhibit endothelial apoptosis either by decreasing the levels of TNF-a,
oxidized LDL and growth factors, or by inhibiting apoptotic pathways.
These anti-apoptotic properties are mediated by constituents within
81
Francis and Pierce
HDL. ApoA1, an important protein of the RCT pathways, diminishes
oxidized LDL and TNF-a induced apoptosis (164-166). Lysosphingolipids
within HDL, such as sphingosylphonphorylcholine and lysosulfatide,
can inhibit growth factor-induced apoptosis as well as directly interfere
with apoptotic signalling within ECs by activating the Akt signalling
pathways (167-169).
Endothelial migration and proliferation is also promoted by HDL.
Endothelial migration is believed to be stimulated by the interaction
between SR-BI and HDL (157). Alternatively, sphingosine-1-phosphate
within HDL can induce endothelial cell migration by activating Ras/
Raf1-dependent ERK (157,167). The induction of EC proliferation by
HDL is mediated by downregulating ADAMTS-1, by activating the
protein kinase C pathway and by increasing intracellular Ca2+ levels
through phospholipase C activation (170-172).
smootH musClE CEll PRoliFERAtioN
ANd REGREssioN
Although there are four known smooth muscle cell subpopulations
(173-175), focus has been placed on understanding two morphologic-
ally distinct subpopulations. The majority of vascular smooth muscle
cells (VSMCs) normally found in the arterial media are elongated and
spindle shaped, forming the classic ‘hills and valley’ growth pattern.
These ‘swirling-type’ VSMCs have a contractile phenotype. VSMCs
with the synthetic phenotype, also known as the ‘epithelioid-type’, are
only present in small proportions within the arterial media. The synthetic
phenotype of VSMC is cuboidal in shape and displays a cobblestone
appearance at confluence. These VSMCs are believed to be the major
VSMC contributor to atherosclerotic plaque progression (176-178).
Akin to macrophages, accumulation of intercellular lipids can change
VSMCs into foam cells, which may be considered a third important
phenotype of VSMC found in atherosclerotic plaques. Moreover, de-
differentiation of VSMC decreases its affinity to HDL, thus effectively
decreasing apo-mediated cholesterol efflux and contributing to the
early events of foam cell transformation (179).
Despite the large amount of evidence linking VSMC to athero-
sclerotic plaque progression, little is known about their involvement
in atherosclerotic plaque regression. Nevertheless, regression can be
induced by the removal of lipids from sterol-loaded VSMC and by the
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