Cardiovascular Research 52 (2001) 372–386
www.elsevier.com / locate / cardiores
Review
Adhesion receptors of vascular smooth muscle cells and their
functions
Elena P. Moiseeva*
Division of Cardiology, Department of Medicine, University of Leicester, Clinical Sciences Wing, Glenfield General Hospital, Leicester LE3 9 QP, UK
Received 9 January 2001; accepted 20 June 2001
Abstract
Vascular smooth muscle cells (SMCs) are present in several phenotypic states in blood vessels. They show a high degree of plasticity,
undergoing rapid and reversible phenotypic changes in response to environmental stresses and vascular injury. Thereby, SMCs play an
important role in development of atherosclerosis and restenosis after angioplasty and coronary bypass grafting. Many functions of SMCs,
such as adhesion, migration, proliferation, contraction, differentiation and apoptosis are determined by surface adhesion receptors
involved in cell–cell binding and interactions between cells and extracellular matrix (ECM) proteins. Some cell adhesion receptors are
involved in intracellular signalling and participate in cellular response to different stimuli. The adhesion receptors of vascular SMCs
discussed here include the ECM adhesion receptors integrins, a-dystroglycan and syndecans, as well as the cell–cell adhesion receptors
cadherins and cell adhesion molecules. This review is intended to provide a generalised overview of the receptors expressed in vascular
SMCs in relation to their functions and implications for vascular pathology.  2001 Elsevier Science B.V. All rights reserved.
Keywords: Extracellular matrix; Receptors; Smooth muscle
1. Introduction
There is a considerable level of heterogeneity of vascular smooth muscle cells (SMCs) in blood vessels. Vascular
SMCs exhibit distinct morphological and functional properties within the same blood vessel [1,2], as well as in
different types of blood vessels, e.g. arteries and veins [3].
The principle function of vascular SMCs is to maintain
vascular tone and resistance. The differentiated SMCs
exhibit a contractile phenotype, and express smooth muscle (SM) specific contractile and cytoskeletal proteins [4].
Adhesion of contractile SMCs to the extracellular matrix
(ECM) is fortified in order to withstand considerable
tensions due to SMC contraction and haemodynamic
Abbreviations: DGPC, dystrophin–glycoprotein complex; ECM, extracellular matrix; ECs, endothelial cells; IAP, integrin-associated protein;
ICAM-1, intercellular cell adhesion molecule-1; PIP2, phosphatidylinositol (4,5)-biphosphate; PKC, protein kinase C; RGD, arginine–glycine–
aspartic acid; SM, smooth muscle; SMCs, SM cells; uPAR, urokinasetype plasminogen activator receptor, VCAM-1, vascular cell adhesion
molecule-1
*Tel.: 144-116-256-3048; fax: 144-116-287-5792.
E-mail address: [email protected] (E.P. Moiseeva).
forces. In addition to integrins and syndecans, found in
non-muscle cell types, contractile SMCs contain a muscle
specific dystrophin–glycoprotein complex (DGPC), linking actin filaments to ECM. The other important function
of SMCs is related to the SMC response to environmental
stresses and the repair of the blood vessel wall after
vascular injury [1,4]. These responses require modulation
of the SM phenotype, synthetic and migratory activities of
SMCs, which in turn need disengagement of adhesion
receptors anchoring cells to ECM during cell contraction.
The dedifferentiated SMCs are motile and express an
altered set of adhesion receptors. Therefore, modulation of
SM phenotype is crucial in the development of many
vascular diseases including atherosclerosis and restenosis
after angioplasty and coronary artery bypass grafting.
To date, the factors and the mechanisms involved in
regulation of SMC phenotype remain obscure. However,
the ECM is likely to play a pivotal role in regulation of
SMC phenotype [5,6]. Vascular contractile SMCs are
embedded in the ECM and surrounded by an incomplete
basement membrane in vivo [7,8]. A basement membrane
Time for primary review 28 days.
0008-6363 / 01 / $ – see front matter  2001 Elsevier Science B.V. All rights reserved.
PII: S0008-6363( 01 )00399-6
E.P. Moiseeva / Cardiovascular Research 52 (2001) 372 – 386
and one of its essential components laminin, surrounding
contractile SMCs in the blood vessels [7,9], play an
important role in the differentiation of SMCs. The temporal phenotypic modulation of SMCs during vascular injury
leads to the destruction of the basement membrane, which
reappears when SMCs revert to the contractile phenotype
[7]. Laminin is also implicated in maintaining the SMC
contractile phenotype in vitro [10–14].
ECM adhesion receptors provide a link between the
cytoskeleton and the ECM in cell–ECM contacts. ECM
adhesion receptors play a major role in SMC adhesion,
although cell–cell adhesion receptors are also found in
SMCs. A vast number of studies has revealed a central role
for integrins in SMC adhesion and related SMC functions.
There is accumulating evidence on the role of cell adhesion molecules for SMCs. Other adhesion receptors,
syndecans, cadherins and a-dystroglycan, have been
studied to a much lesser extent, although a-dystroglycan is
likely to be relevant to SM contraction. This review
focuses on adhesion receptors including integrins, adystroglycan, syndecans, cell adhesion molecules and
cadherins with an intention to relate expression of the
373
receptors to their functions in a specific SM phenotype
and / or a particular pathophysiological process. Fig. 1
schematically shows some of the information presented
below.
2. SMC integrins
Integrin receptors are the principle receptors for the
ECM and serve as a transmembrane link between the ECM
and the actin cytoskeleton (Fig. 2). Integrins are bound to
an intracellular protein complex, which includes the cytoskeletal proteins talin, vinculin, a-actinin and filamin [15],
in adherens junctions of SMCs. Integrins are composed of
a and b subunits. Each ab combination has its own
ligand-binding specificity [16,17] and signalling properties
(reviewed in [18,19]).
The main integrin ligands are ECM proteins, although
some integrins also interact with other transmembrane
counter-receptors and mediate cell–cell interactions. Integrin–ligand binding is tightly regulated via conformational
changes of integrins by cell signalling. Resting, inactive
integrins have low affinity for their ligands. Integrins in an
active state bind to their ligands with high affinity. Integrin
activation increases integrin affinity and, thereby, regulates
SMC functions, such as adhesion, migration and proliferation (see below).
2.1. Integrin expression in vascular SM related to the
SMC phenotype and interactions of SMCs with other cell
types via integrins
Fig. 1. Schematic representation of phenotypic modulation of smooth
muscle (SM) cells, resulting in the shift in the expression pattern of
adhesion receptors. The adhesion receptors, specifically expressed in a
particular SM phenotype, are shown. Other receptors are shown in Table
2. Left side: differentiated contractile SM cells express integrins a1b1
and a7b1 and the dystrophin–glycoprotein complex (DGPC) with adystroglycan. Integrins localise in the adherens junctions on longitudinal
ribs of cells (shown in black) (after [128]). The DGPC is found in
caveolar domain of cells (shown in grey) between the ribs. Vascular injury
and atherogenesis cause SMC dedifferentiation. Integrins avb1 and avb3
are involved in phenotypic modulation of SM cells. Right side: dedifferentiated SM cells have rearranged the cytoskeleton and adhesion
apparatus. They express integrin a4b1 and cell adhesion molecules
VCAM-1 and ICAM-1, responsible for interaction between SMCs and
other cell types. Integrin a4b1 and VCAM-1 may be involved in SM
differentiation.
Integrins expressed in vascular SM are shown in Table
1. Integrins b1 are predominant in vascular SM in vivo and
in cultured SMCs [26,32]. They are present in the activated
high affinity form in arteries [65]. Vascular injury reduces
expression of total and activated b1 integrin in neointima
[65]. Deactivation of b1 integrins correlates with increased
proliferative and migratory activities of SMCs [65,66].
Hence, expression of activated b1 integrins may contribute
to maintaining the contractile SM phenotype.
The major a integrin subunits present in vascular SM in
vivo are a1, a3 and a5 [26,29]. Expression of a1b1 and
a7b1 integrins correlates with the differentiated SM
phenotype [20,47]. Integrin a7b1 is known to inhibit
surface expression of other b1 integrins in non-muscle cell
types [45,67], therefore, it may influence expression of
other integrins in contractile SMCs. Noteworthy, both
a1b1 and a7b1 bind to laminin, which is involved in
maintaining the contractile SM phenotype. Interestingly,
the promoter of the a1 integrin subunit gene is more active
in differentiated SMCs [68], which may account for huge
variations in reported levels of a1b1 integrin.
In contrast to a1b1, a4b1 integrin is not expressed in
differentiated SM, but is expressed in developing blood
vessels, where it co-localises with its ligand cellular
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E.P. Moiseeva / Cardiovascular Research 52 (2001) 372 – 386
Fig. 2. Schematic drawings of cell–ECM adhesion complexes of smooth muscle cells. ECM proteins collagen (COL), fibronectin (FN), laminin (LN),
tenascin (TC), thrombospondin (TSP) and fibrinogen (FG) are shown. Black lines extending from adhesion receptors indicate polysaccharide chains in
proteoglycans. (A) The extracellular domains of integrins and syndecans interact with ECM proteins. The intracellular domains of integrins and syndecans
bind to cytoskeletal proteins linking adhesion receptors to the actin filaments. (B) a-Dystroglycan (aDG) interacts with the C-terminal part of a chain of
LN, a1b1 and a2b1 integrins interact with the N-terminal part of a chain of LN. In the dystrophin–glycoprotein complex, a-dystroglycan binds to a
complex of integral membrane proteins b-dystroglycan (b-DG), b-, d- and e- sarcoglycans and sarcospan (SP); they bind to dystrophin (D). Dystrophin
has several actin-binding sites and provides the connection to the actin filaments. (C) ICAM-1 interacts with FG. The intracellular domain of ICAM-1
binds to cytoskeletal proteins linking it to the actin filaments.
fibronectin and a counter-receptor vascular cell adhesion
molecule-1 (VCAM-1) [37,38]. This integrin binds to an
additional site of fibronectin, encoded by an alternatively
spliced exon. Expression of a4b1 integrin and VCAM-1 is
a prerequisite for expression of SM phenotype markers in
human cultured SMCs [38]. This integrin is also found in
atherosclerotic intimal thickening together with VCAM-1
(see below) and may be involved in cell–cell interactions
between SMCs and VCAM-1-expressing endothelial cells
(ECs) [38]. Since another integrin, a9b1, also binds to
VCAM-1 [54] and is expressed in vascular SM [55], it
may mediate interactions between SMCs and VCAM-1expressing ECs.
Integrins av are expressed in the blood vessel wall,
although they are not the major integrins. Expression of
avb3 integrin varies dramatically in SMCs of different
origin [57,58]. Microscopic studies have shown co-localisation of integrins avb3 and avb5 with their ligand
vitronectin in the atherosclerotic intima [60]. Some ECM
ligands for avb3, such as fibrin, fibrinogen, thrombospondin, vitronectin and osteopontin, are not detectable in
normal blood vessels and found only in diseased blood
E.P. Moiseeva / Cardiovascular Research 52 (2001) 372 – 386
375
Table 1
Integrin expression in vascular smooth muscle
a
b
ECM ligands
and
counter-receptors
Ligand recognition of
isolated SM integrins
or integrins on
SMC surface
Expression in SM in vivo
and in non-cultured isolated
vascular SMCs
Expression in
cultured
vascular SMCs
a1
b1
COL I, COL II,
COL III, COL IV,
LN 1
COL I, COL II,
COL III, COL IV,
LN 1 [20–23];
COL VIII [24]
Upregulated in developing aorta; high
expression in human media in aorta,
coronary arteries and other vascular SM;
reduced expression in intimal thickening
in human aorta [20,25–29]. Low or no
expression in rat carotid artery or aorta,
but high expression after injury [30]
Present in SMCs [21,31–33]
Expression decreased in cultured
SMCs to undetectable levels [20,26]
Modulated expression [34]
a2
b1
COL I, COL IV,
LN
COL I [22,23];
COL VIII [24]
Expressed in ductus arteriosus [28]. Not
expressed in other vascular SM [26,29,30]
Expressed in SMCs [22,23,26,29,33]
a3
b1
LN, FN, COL I;
LN 2, LN 4,
LN 5,
not FN [35]
FN, COL I [22,23]
Expressed in human media in aorta, coronary
arteries and other vascular SM [25,26,28,29]
Only a3A isoform is expressed, not a3B [35]
Expressed in SMCs at high
levels [22,23,26,29,32,33]
a4
b1
VCAM-1, cell-FN;
OSP [36]
Expressed in newly formed blood vessels, in
atherosclerotic intima, human embryonic
aorta, but not adult aorta [26,37,38]
Not expressed [26]. Expressed in
newborn ductus arteriosus SMCs [33]
a5
b1
FN;
tOSP [39]
FN [22,23];
FB [33]
Found in the media of human normal and
atherosclerotic coronary artery, aorta and
other vascular SM [26,28,29,40]. Not
found in the rat normal carotid artery, its
expression was induced after a vascular
injury in SMCs at the lumenal surface
of the neointima [41]
Abundant in SMCs [22,26,29,32,33]
Modulated expression [34]
a6
b1 /
b4
LN 1; LN 8 [42]
LN 1 [43]
Found in ductus arteriosus SM and in
small vessels [28,44]. Not expressed
in aortic SM [26]
Not expressed [26,33]. Expressed in
foetal ductus arteriosus SMCs [43]
a7
b1
LN 1; LN 2,
LN 4 [45]
LN 1 [22,46]
Expressed at high levels in vascular
SM [47]. Only a7B isoform is
expressed in SM [47]
Expressed in foetal ductus arteriosus
SMCs [22]. Downregulated in
cultured aortic SMCs [47]
a8
b1
FN, TN, VN,
not OSP [48];
OSP [49]
Predominantly expressed in SM [50]
Expressed in aortic SMCs [30]
a9
b1
TN [51]; tOSP [52,53];
VCAM-1 [54]
Expressed in vascular SM [55]
Not expressed in newborn
ductus arteriosus SMCs [33]
av
b1
VN, FN; agrin [56]
VN, FN [22];
OSP [57]
av
b3
VN, FG, vWF, FN,
LN, OSP, TSP,
dCOL, PLC
VN, FN, LN 1,
COL I, COL IV
[22,43];
OSP [57,58];
FB [33]
Expressed in media of human normal
and atherosclerotic arteries and ductus
arteriosus [28,59,60]. Very early
upregulated after injury [61,62]
Detected only in neointimal
SMCs of injured arteries [63]
Expressed in vascular SMCs
[22,26,32,33,64]. Varied
expression levels in SMCs
from different sources [57,58]
av
b5
VN, OSP
VN, OSP [57,58]
Expressed in ductus arteriosus and
atherosclerotic intima [28,60]
Very early upregulated after injury [62]
Expressed in SMCs [33,57,58,64]
Expressed in foetal ductus
arteriosus and other vascular
SMCs [22,57]
Data contradicting previous reports are shown in italics. Conflicting data have been reported on the expression of a1, a5 and avb3 integrins; these
discrepancies are likely to be caused by differences in detection levels, variations between species or variable levels of integrin expression in SMCs from
sources of different origin. Integrin specificity is indicated as presented before [16,17]. Newly described and SM integrin ligands are presented with
references. COL, collagen; dCOL, denatured COL; FB, fibrin; FG, fibrinogen; FN, fibronectin; LN, laminin, PLC, perlecan; OSP, osteopontin; TN,
tenascin; tOSP; thrombin-cleaved OSP; TSP, thrombospondin; VN, vitronectin; vWF, von Willebrand factor.
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E.P. Moiseeva / Cardiovascular Research 52 (2001) 372 – 386
vessels [60,69–72]. Integrins avb3 and avb5 are upregulated early after vascular injury and are likely to be
involved in postangioplasty events and neointima formation [62].
2.2. Adhesion, migration, ECM assembly and ECM
contraction
Integrins b1 are considered to play a major role in
adhesion [22], ECM assembly, repair and remodelling.
Several SMC integrins bind to laminin, but only a7b1
integrin has been shown to affect laminin adhesion in
SMCs [47]. Integrin a7b1 also plays an important role in
laminin polymerisation [73]. Among integrins a1b1, a2b1
and a3b1, involved in collagen adhesion, only a1b1 and
a2b1 are responsible for collagen contraction
[23,30,31,74]. Since only a1b1 is expressed in vivo, it is
likely to be involved in collagen remodelling after vascular
injury.
Adhesion to fibronectin is mediated by integrins a3b1
and a5b1 [23,74]. Integrin a5b1, highly abundant in
cultured SMCs, is also involved in fibronectin polymerisation [41]. This has important implications for SMC
proliferation, since inhibition of the fibronectin matrix
assembly inhibits proliferation of human primary SMCs
[75]. After vascular injury, a5b1 is induced at the lumenal
surface of neointima and may be involved in blood vessel
wall repair and incorporation of plasma fibronectin into
ECM [41]. Recently this integrin has been implicated in
fibrin adhesion and fibrin clot contraction [33]. Since fibrin
is present in atherosclerotic plaques [69] and fibrinogen is
abundant in the intima of atherosclerotic aorta [70], a5b1
integrin is thought to cause vessel narrowing during the
progression of atherosclerosis [33]. The other fibrin-binding integrin avb3 is implicated only in fibrin adhesion, but
not in fibrin clot contraction [33,76]. Recent data on a5b1
and avb3 integrins indicate that migration of SMCs into
fibrin clot may require co-operation of both integrins [77].
Integrins b1 are implicated in migration of cultured
SMCs [22,66,78,79]. Among b1 integrins, only a2b1,
a5b1 and a7b1 are known to participate in SMC migration and motility [26,47,77,79,80]. In contrast to b1
integrins, avb3 is implicated in SMC migration both in
vitro [32,57,58,77–79,81–85] and in vivo [61,83,86,87]. A
blockade of avb3 integrin with cyclic arginine–glycine–
aspartic acid (RGD) peptide or RGD mimetic in animal
vascular injury models reduces vessel wall thickening
[61,83,86,87]. Recent investigations have demonstrated
that this effect may be also related to apoptosis (see
below).
While all av-containing integrins interact with vitronectin and osteopontin and are involved in the adhesion to
these ECM proteins, only avb3 is implicated in SMC
migration [57,58,84]. SMCs, which express avb5 integrin
and do not express avb3, do not migrate to osteopontin
[57,58].
2.3. Integrin signalling in cell adhesion, proliferation,
apoptosis and other SMC functions
Integrins participate in several signalling pathways.
Integrin ligation and clustering in response to the ECM
initiate an assembly of integrin-cytoskeleton complexes to
support cell adhesion. Several integrin-associated proteins,
such as urokinase-type plasminogen activator receptor
(uPAR), integrin-associated protein (IAP) and tetraspanin
CD9, modulate integrin-mediated adhesion in SMCs. The
uPAR associates with and stabilises b1 integrin–caveolin
complexes in human SMCs; this association is required for
b1 integrin-mediated SMC migration [88–90]. SMC migration to collagen is potentiated by thrombospondin via
thrombospondin-binding IAP, which is associated with
a2b1 integrin in SMCs [91,92]. In human vascular SMCs,
CD9 is mainly associated with a2b1, a3b1 and a5b1
integrins and affects collagen gel contraction [93].
Some integrins participate in another category of signalling leading to cell proliferation, differentiation and
apoptosis (reviewed in [18,19]). Integrins also contribute to
the cell response to growth factors. Integrin-mediated
signalling, which is related to these SMC functions, is
summarised below.
Integrins av affect many functions of SMCs in contrast
to other integrins. Integrin avb3 together with a5b1
affects Ca 21 influx in arteriolar SMCs, indicating the link
through intracellular signalling pathways to the Ca 21
channels [94,95]. Blocking avb3 integrin causes a decrease in Ca 21 influx in parallel to the arteriolar lumen
diameter increase [94]. Therefore, the effect of avb3
integrin on arteriolar vasodilation in response to tissue
injury, observed earlier [96], may be mediated by avb3
integrin signalling involving Ca 21 . Another intriguing
example of integrin-mediated signalling involves SMC
dedifferentiation induced by serum or vitronectin, abundant in serum, but the underlying mechanisms remain
obscure. SMC adhesion to ligands from whole serum or
vitronectin via integrin avb1 inhibits SMC contractility.
Blocking vitronectin with specific antibodies or RGDcontaining peptides diminishes the loss of SMC contractility in cell culture [97].
Integrin avb3 has been implicated in SMC proliferation
in response to several stimuli. Integrins avb3 and avb5
augment the mitogenic response to cyclic stretch, mediated
by PDGF [64]. Integrin avb3 enhances proliferative and
other responses of SMCs to growth factors [82,85,98,99]
and modulates proliferation induced by thrombospondin
[63]. The exact mechanisms of these co-operative effects
are not clear, but the physical association between growth
factor receptors and avb3 in other cell types has been
confirmed, linking the growth factor and avb3 integrin
signalling pathways [100,101].
Recently a new wave of research has demonstrated the
importance of cell adhesion in apoptosis. The role for
avb3 integrin in SMC apoptosis has been studied to
E.P. Moiseeva / Cardiovascular Research 52 (2001) 372 – 386
provide insight into the mechanisms of restenosis. The
blockade of avb3 integrin in an animal model of vascular
injury reduces intimal thickening, which correlates with
abundant apoptosis in injured vessels [102,103]. The avb3
integrin-mediated signalling in apoptosis may be also
relevant to plaque stability, since blocking of avb3
integrin with the peptide products of ECM degradation
may lead to SMC apoptosis and promote plaque rupture.
3. Dystrophin–glycoprotein complex
The dystrophin–glycoprotein complex (DGPC) is expressed in all types of muscle and is critical for muscle
function. Mutations in genes encoding DGPC components
lead to different forms of muscular dystrophy and cardiomyopathy [104–107]. The function of the DGPC is to
provide mechanical stability of the cell membrane during
contraction and protect cells from overstretching [108–
111]. The importance of this complex for vascular SM has
just started to be unravelled.
The DGPC serves as a link between the basement
membrane around muscle cells and the actin filaments
(Fig. 2B). The cell surface receptor for the DGPC is a
proteoglycan, called a-dystroglycan. It connects other
components of the DGPC and laminin and perlecan
[112,113], which are essential ECM components produced
by vascular SMCs [9,25,114,115]. a-Dystroglycan is also
involved in the laminin assembly on cell surfaces followed
by incorporation of other ECM proteins, such as perlecan
and collagen IV, to form a basement membrane [73,116].
An antibody blocking study has revealed that laminin
polymerisation by myoblasts is supported much more by
a-dystroglycan than by b1 or a7 integrins [73]. Studies of
a-dystroglycan null mice and a-dystroglycan-deficient ES
cells also indicate that a-dystroglycan is indispensable in
basement membrane assembly compared with a7b1 integrin [116–118].
a-Dystroglycan is an extracellular protein in contrast to
other integral membrane adhesion receptors. It binds to a
transmembrane protein b-dystroglycan in complex with
several other transmembrane proteins, sarcoglycans and
sarcospan (reviewed in [104,119]). Sarcoglycans contribute
to stability of the whole DGPC [111,120] and cell membrane [110,111]. Thus, several proteins in the DGPC
provide a durable link between the ECM and intracellular
proteins, whereas this is the function of an adhesion
receptor in other ECM adhesion complexes. For this
reason, it seems feasible to consider the functioning of the
DGPC as a whole unit, rather than to consider the function
of a-dystroglycan alone.
The SM DGPC consists of a- and b-dystroglycans, b-,
d- and e-sarcoglycans, sarcospan and dystrophin [121,122].
The SM DGPC differs from that in striated muscle, which
contains a different set of sarcoglycans: a, b, g and d
[121,122]. There are two differently glycosylated a-
377
dystroglycan isoforms, 100- and 156-kDa, in SM [121].
The 156-kDa isoform is a component of the DGPC [121].
Dystrophin expression strongly correlates with the contractile performance of vascular SM both in vivo and in vitro
[123–125]. Dystrophin is not expressed in cultured SMCs
in the presence of serum [123], which causes SMC
dedifferentiation. In vivo, dystrophin is found in the
caveolar domain of SMCs outside integrin-containing
adherens junctions [126–128].
In parallel to the DGPC in SMCs, there is another
complex with utrophin [122], which has been studied to a
lesser extent than the DGPC. Utrophin is ubiquitously
expressed in cells, including vascular SMCs [125,129];
therefore, in contrast to dystrophin, it is not related to
muscle contraction. The utrophin glycoprotein complex in
SM is likely to include 100-kDa a-dystroglycan and bdystroglycan [121,122]. In cultured aortic SMCs, utrophin
co-localises with a-dystroglycan in the focal adhesions,
containing b1 integrin and the cytoskeletal protein vinculin
[130]. Recently a new dystrophin / utrophin-binding protein
aciculin has been characterised in SM [131,132]. Aciculin
(also called PGMRP) is expressed predominantly in vascular and visceral SM and to a lesser extent in cardiac muscle
in humans [132]. Aciculin expression strongly correlates
with the differentiated contractile SM phenotype
[132,133]. Aciculin is likely to be involved in cell adhesion, as it co-localises with dystrophin, utrophin and adystroglycan in adhesion structures of muscle cells
[130,131], but whether PGMRP has structural, signalling
or other function is unknown.
The role of a-dystroglycan in SMC adhesion has not
been studied, although the effect of other proteins of the
DGPC on SM is known. In mdx mice, with the inactivated
dystrophin gene, the mechanical activities in portal vein
were severely disrupted [134]. Duchenne muscular
dystrophy patients (with the mutated dystrophin gene)
undergoing surgery tend to bleed more during surgery
compared with other patients [135]. Mutations in the
sarcoglycan genes in limb-girdle muscular dystrophy patients [107] lead to vascular SM dysfunction and an
increased baseline of myocardial blood flow [136]. In both
groups of patients vascular abnormalities are likely to be
caused by weakness of vascular vessel walls and a poor
vascular SM vasoconstrictive response due to mutations in
the dystrophin and sarcoglycan genes.
Recently the importance of DGPC for vascular smooth
muscle has been demonstrated directly in animal models
with mutated DGPC components [120,137–139]. Mouse
and BIO14.6 hamster animal models deficient in d-sarcoglycan develop cardiac abnormalities caused by primary
vascular dysfunction [137]. The d-sarcoglycan-null mutation leads to irregularities of the coronary arteries, which
trigger the onset of myocardial necrosis in mice [137,140].
The b-sarcoglycan-deficient mice develop vascular constrictions in the heart, diaphragm and kidneys, which result
in muscular dystrophy and cardiomyopathy with focal
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E.P. Moiseeva / Cardiovascular Research 52 (2001) 372 – 386
areas of necrosis, associated with the disrupted DGPC in
all muscle types [120]. Thus, mutations in b- and dsarcoglycans in mice perturb vascular function, which in
turn initiates cardiomyopathy.
4. Syndecans
Syndecans are members of a proteoglycan family of
adhesion transmembrane receptors with the glycosaminoglycan chains covalently attached to the extracellular part
of the receptor (reviewed in [141,142]). There are four
known mammalian syndecans. Syndecans bind to a variety
of ECM proteins (Fig. 2A), cell adhesion molecules,
growth factors, lipoproteins, lipoprotein lipases and components of the blood-coagulation cascade. To date, all
known syndecans interact with their ligands via polysaccharide chains, although syndecan-4 may also support cell
adhesion by a protein core [143]. These receptors play
important roles in cell–ECM and cell–cell adhesion and
migration (reviewed in [141,142,144]). Syndecans are
thought to be co-receptors providing additional sites for
ECM ligands in order to increase the strength of cell
adhesion (Fig. 2A).
All syndecans bind to PDZ-containing proteins (the
PDZ domain is called after proteins PSD-95 / DlgA / ZO-1,
where it was originally found) linking syndecans to the
cytoskeleton [145]. Syndecan-4 is consistently found in
focal adhesions of several cell types, including SMCs
[146]. Recent data have implicated syndecans, and
syndecan-4 in particular, in the assembly of focal adhesions and actin cytoskeleton [147–152]. Similar to integrins, syndecans are involved both in cytoskeleton and
ECM assembly. Syndecan-2 affects the assembly of
laminin and fibronectin fibrils and can override the function of activated integrins in ECM assembly [153]. Growing evidence suggests that syndecans are involved in cell
signalling. Syndecan-4-mediated signalling involves protein kinase PKCa and phosphatidylinositol-4,5-biphosphate (PIP2) via direct binding of syndecan-4 to PKCa
and PIP2 (reviewed in [145,154]).
An intriguing feature of syndecans is their involvement
in other cellular functions, such as proliferation, growth
factor signalling and lipid metabolism (reviewed in
[141,142,144]). Syndecans bind to the heparin-binding
growth factors, such as basic FGF, VEFG and EGF, and
provide secondary binding sites for them on the cell
surface. Therefore, syndecans may be involved in mediating growth factor-induced responses in vascular SM.
Syndecans, in particular syndecan-1, may also participate
in lipid metabolism, as syndecan-1 may mediate LDL
receptor-independent clearance of lipoproteins via binding
to lipoprotein lipase, an enzyme involved in triglyceride
catabolism [155].
All four known syndecans are expressed in normal
arterial SMCs [156]. Syndecan-1 is enriched in the whole
artery, syndecans-2 and -4 are enriched in the medial layer.
The arterial medial layer contains most of syndecan-1 and
syndecan-4 mRNA. In contrast to syndecan-2 and -3,
syndecan-1 and -4 are increased after arterial injury in
animal models [156,157]. Since syndecans participate in
the ECM assembly, they may be involved in the ECM
repair after vascular injury. Syndecan-1, -2 and –4 are
expressed in cultured vascular SMCs [156,158,159]. Expression of syndecan-1 and -4 varies in cultured SMCs in
response to serum and growth factors, while syndecan-2 is
expressed constitutively. The significance of syndecans in
SMC adhesion and migration has not been studied.
Since syndecans bind to growth factors, lipoprotein
lipases and components of the blood-coagulation cascade,
they may have pleiotropic effects on SMC functioning.
Thrombin treatment of vascular SMCs augments expression of syndecan-1, exhibiting high affinity antithrombin
III-binding activity [160]. Therefore, SMCs could play an
important role in controlling local thrombus formation
subsequent to vascular injury, via a feedback mechanism
that involves thrombin-induced stimulation of SMC surface syndecan-1 expression, which generates anticoagulant
activity via binding of antithrombin III, an inhibitor of
thrombin activity [160].
5. Cell adhesion molecules
Cell adhesion molecules belong to the immunoglobulin
family of cell–cell adhesion receptors with a transmembrane domain. There is not much known about the link
between these receptors and the actin cytoskeleton. Intercellular cell adhesion molecule (ICAM-1) is known to
interact with the cytoskeletal proteins a-actinin and ezrin
[161,162]. Two adhesion molecules VCAM-1 and ICAM-1
have been detected in vascular SM. VCAM-1 is a counterreceptor for the a4b1, a9b1, a4b7 and aDb2 integrins,
present on lymphocytes and monocytes [54,163,164].
ICAM-1 interacts with b2 integrins, present on neutrophils, monocytes and lymphocytes [163,165]. ICAM-1 also
binds to fibrinogen and, thereby, can participate in ECM–
cell interactions [166–168] (Fig. 2C). The expression of
VCAM-1 and ICAM-1 in vasculature and their potential
roles in the development of atherosclerosis were thoroughly reviewed recently [169].
VCAM-1 is found in human foetal aortic SMCs expressing a4b1 integrin (see above), but not in the normal adult
aortic media [38]. VCAM-1 expression in SMCs in
atherosclerotic lesions is well-documented [170–172].
VCAM-1 is also upregulated in SMCs after vascular injury
and co-expressed with monocyte chemotactic protein
(MCP)-1 in SMCs within 4 h of injury [173]. Macrophage
infiltration occurs in parallel with the expression of
VCAM-1 and MCP-1; these inflammatory cells are present
on the lumenal surface of injured vessels during intimal
lesion formation [173]. Similar to VCAM-1, ICAM-1 is
E.P. Moiseeva / Cardiovascular Research 52 (2001) 372 – 386
expressed in atherosclerotic SMCs, but not in normal
contractile SMCs [172]. ICAM-1 is induced in SMCs of
saphenous vein after culturing with serum or TNF-a ex
vivo [174]. ICAM-1 expression in vitro is phenotypedependent and can only be induced in SMCs with decreased or modulated myofilament volume [175]. In cultured SMCs expression of VCAM-1 and ICAM-1 can be
induced by cytokines [170,176–178]. Increased surface
expression of VCAM-1 and ICAM-1 on SMCs leads to
augmented adhesion of a4 integrin-positive lymphocytes
and b2 integrin-containing monocytes [178,179]. Since the
expression of VCAM-1 and ICAM-1 can be induced by
cytokines in SMCs, these adhesion molecules are likely to
play important roles in the pathophysiology of inflammatory and immune processes in atherosclerosis by enabling
leukocyte trafficking within atherosclerotic vascular tissue.
ICAM-1 expression of SMCs affects not only adhesion
of monocytes, but also expression of tissue factor and
procoagulant activity of monocytes [180]. Thereby, the
interactions between monocytes and ICAM-1-expressing
SMCs within atherosclerotic plaques would increase the
thrombogenic properties of the plaques; in the case of
plaque rupture it would lead to thrombus formation and
SMC adhesion to fibrinogen via integrins and ICAM-1.
Since ICAM-1 participates in cell signalling in other cell
types, SMC adhesion to fibrinogen via ICAM-1 may lead
to other events. ICAM-1 ligation induces VCAM-1 expression in ECs [181]. Interaction between ICAM-1 and
fibrinogen results in proliferation and increased cell survival of non-SMCs [182,183]. Ligation of fibrinogen to
ICAM-1 on the cell surface of ECs stimulates the tyrosine
phosphorylation of several proteins involved in signalling
[183,184]. As mentioned above, fibrinogen is abundant in
the intima of atherosclerotic aorta, where SMCs express
ICAM-1. The effect of fibrinogen on SMCs expressing
ICAM-1 remains to be investigated.
6. Cadherins
All cadherins, except T-cadherin, belong to a family of
transmembrane Ca 21 -dependent homophilic cell–cell
adhesion receptors. T-Cadherin is anchored to the cell
membrane via glycosylphosphatidylinositol. N- and Rcadherins can also support heterophilic adhesion [185].
Cadherin homodimers form a ‘zipper’ structure at the
intercellular contact zone on the cell surface [186]. These
receptors bind to the cytoplasmic plaque proteins catenins,
which provide a link with vinculin and the actin cytoskeleton. Cadherins are involved in signalling mediated by
b-catenin (reviewed in [186,187]). Expression of N-, Rand T-cadherins has been reported in normal vascular
SMCs [188–192]. Cadherin 6B, expressed in chicken
aorta, is characterised as a specific marker for differentiated SM phenotype [193].
N-Cadherin is expressed at a higher level in human
379
venous SM compared to arterial SM [194]. In rat aorta
N-cadherin is found in a population of SMCs adjacent to
ECs [188]. An anti-N-cadherin antibody inhibits adhesion
between SMCs and ECs in a Ca 21 -dependent manner,
indicating that N-cadherin may mediate EC–SMC interactions in vivo [188]. However, as ECs are separated from
the SM layer by the basement membrane, they can only be
in contact with SMCs after vascular injury and in ulcerated
atherosclerotic plaques.
T-Cadherin was originally identified as a novel lipoprotein-binding protein in a membrane fraction of aortic
SMCs [190]. T-Cadherin amounts are significantly higher
in fatty streaks and aortic fibrous plaque tissue compared
to normal aorta [195]. The expression of T-cadherin is high
in vascular SMCs, but reduced by 75% in culture
[194,195]. T-Cadherin expression is cell density dependent
with the highest level in confluent cells and is downregulated by serum and growth factors [196,197].
In contrast to other cadherins, E-cadherin is not found in
normal vascular SMCs, but the majority of atherosclerotic
lesions contain cells positively stained for E-cadherin
[198]. In atherosclerotic intima, E-cadherin is expressed by
intimal cells showing varying degrees of transformation
into foam cells [198]. After balloon injury an increased
level of E-cadherin coincides with the initiation of SMC
proliferation, whereas the levels of R- and T-cadherins
temporarily decrease [192].
Since normal contractile SMCs are surrounded by ECM,
SMC adhesion to ECM is predominant in vascular SM,
although cell–cell contacts may increase during tissue
remodelling or in vascular injury, when the basement
membranes, underlying ECs and around SMCs, are degraded or damaged. Cadherin expression in adult vascular
SMCs seems to be to some extent redundant, however, in
other cell types E- and N-cadherins are implicated in
contact inhibition of growth [199,200]. Furthermore, Ecadherin is also implicated in a physiological pathway
required for cell survival [201]. Therefore, the significance
of cadherin interactions in normal and especially
pathological conditions, such as vascular injury with
induced ECM rearrangement, SMC migration and proliferation, requires further investigation.
7. Closing remarks
The data, summarised in this review, demonstrate the
fundamental importance of cell adhesion receptors in the
physiology of vascular SM. SMCs use a range of adhesion
receptors involved in diverse biological functions of SMCs
under normal and pathological conditions, such as vascular
injury and atherosclerosis (summarised in Table 2).
A growing body of evidence indicates that cell adhesion,
spreading, migration and ECM assembly involve several
types of adhesion receptors. Some types of adhesion
receptors can regulate other types and / or may require
E.P. Moiseeva / Cardiovascular Research 52 (2001) 372 – 386
380
Table 2
Involvement of adhesion receptors in smooth muscle functions in atherosclerosis and vascular injury
Adhesion
receptors
Normal vascular SM
Vascular injury
Atherosclerosis
Integrins
Activated b1 integrins are
predominant [26,32,65]
a5b1 and a7b1 participate
in the assembly of FN and
LN matrices, respectively
[41,73]
Reduced expression of total and activated b1
integrin in neointima enables SMC proliferation
and migration [65,66]. a5b1 is induced at the
luminal surface of the neointima and participates
in the incorporation of plasma FN into ECM to
repair blood vessel wall [41]. a5b1 may be involved
in FB clot contraction on the damaged surface of the
blood vessel wall [33]. a1b1 may be involved in COL
remodelling after vascular injury repair [30] avb1 inhibits
SMC contractility in SMC exposed to serum [97]
Upregulated avb3 is involved in SMC migration
[61,83,86,87] and apoptosis [102,103]
a4b1 and a9b1 may enable interactions
between SMCs and VCAM-1-expressing
ECs [38,54]. a5b1 may cause vessel
narrowing during the progression of
atherosclerosis due to FB contraction [33]
avb3 enhances SMC proliferative and other
responses to TSP and growth factors [82,85,98,99]
avb3 may cause SMC apoptosis, when blocked
with the peptide products of ECM degradation,
and promote plaque rupture
a-Dystroglycan
a-Dystroglycan is essential
for the assembly of the cell
basement membrane [73,116,117]
DGPC may be involved in
SM contractility [123,124]
Vascular injury in patients with Duchenne muscular
dystrophy leads to extensive bleeding [135]
Exposure to serum abolishes
dystrophin expression [123]
Syndecans
All four syndecans are
expressed [156]
Syndecan-1 and -4 are upregulated [156,157] and
may be involved in the ECM assembly and repair
after vascular injury. In SMCs exposed to thrombin,
syndecan-1 expression increases anticoagulant
activity [160]
Syndecan-1 may be involved in triglyceride
catabolism via binding to lipoprotein
lipase [155]
CAMs
VCAM-1 and ICAM-1 are
not found [38,172]
VCAM-1 is present in parallel with macrophage
infiltration to enable macrophage
trafficking [173]
VCAM-1 and ICAM-1 are expressed [170–172]
and participate in inflammatory and immune cell
trafficking [178,179] within atherosclerotic tissue
SMC ICAM-1 induces procoagulant activity of
monocytes and increases thrombogenic properties
of atherosclerotic plaques [180]
Cadherins
N-, R- and T-cadherins and
cadherin 6B are expressed
[188–193]
E-Cadherin expression increases,
the levels of R- and T-cadherin
decrease [192]
E-Cadherin is expressed [198]
T-cadherin is markedly upregulated [195]
Lipoprotein-binding T-cadherin may be
involved in lipid metabolism
Abbreviations as in Table 1.
co-operation with other types of adhesion receptors. Some
integrins can regulate expression and activity of other
integrins [45,67] and N-cadherin [202] or require cooperation with other integrins [77] and syndecans
[150,152,153]. Syndecans are known to affect both integrins and cadherins [203]. ICAM-1 ligation induces expression of the other adhesion receptor VCAM-1 [181]. Such
interactions between adhesion receptors in SM have not
been studied; nevertheless they may be significant for the
co-ordinated cell–cell and cell–ECM adhesion during
vascular injury and / or in development of vascular diseases.
In conclusion, the following points should be emphasised
1. Laminin, found in the basement membrane around
SMCs, plays the pivotal role in SMC differentiation.
Adhesion receptors to laminin, integrins a1b1 and
a7b1 and a-dystroglycan in the DGPC, are expressed
only in contractile SMCs. While the adhesion receptor
responsible for maintaining the SM contractile pheno-
type has not been identified, a-dystroglycan is indispensable for the laminin assembly.
2. Integrins a1b1 and a5b1 are likely to participate in
collagen remodelling and fibrin clot contraction, respectively, after vascular injury. ECM remodelling activities
of these integrins within the blood vessel wall may
cause blood vessel narrowing.
3. Although integrin avb3 is expressed both in normal
and diseased blood vessels, some ECM ligands of avb3
(thrombospondin, vitronectin, osteopontin, fibrin and
fibrinogen) are found only in injured or diseased blood
vessels. Furthermore, this integrin is also involved in
signalling. For these reasons, SMC adhesion via avb3
may have a profound effect on many other SMC
functions, such as migration, proliferation and apoptosis
in vascular injury. Blocking of the integrin avb3 with
products of degradation of ECM proteins may contribute to apoptotic process within the atherosclerotic tissue
and affect plaque stability. The adhesion and signalling
properties of avb3 integrin ensure its unique role in
pathophysiological conditions.
E.P. Moiseeva / Cardiovascular Research 52 (2001) 372 – 386
4. Adhesion receptors ICAM-1, VCAM-1 and integrin
a4b1 are expressed in adult vascular SM only in
pathological conditions. These receptors may participate
in SMC interactions with ECs and leukocytes. ICAM-1
and VCAM-1 expressed on SMC surface may contribute to inflammatory and immune cell trafficking within
atherosclerotic tissue. ICAM-1 expression in SMCs
may also increase thrombogenic properties of atherosclerotic plaques due to the increased production of
tissue factor in monocytes.
5. Some adhesion receptors, such as cadherins and
syndecans, may have important additional roles, e.g.
syndecan-1 and T-cadherin in lipid metabolism,
syndecan-1 in anticoagulant activity.
It is becoming clear that cell adhesion is a complex
process with many players. The research on the role of
integrins in SMC adhesion has dominated the field. There
is an urgent need to accelerate research on other SM
adhesion receptors, especially ECM receptors syndecans
and a-dystroglycan, and the interactions between various
types of receptors in order to understand in depth the
functioning of vascular SM in norm and disease.
[9]
[10]
[11]
[12]
[13]
[14]
[15]
[16]
[17]
[18]
Acknowledgements
[19]
The author would like to warmly thank Professor A.C.
Newby for helpful discussion and critical comments on the
manuscript. The author would like to thank E. Coates and
departmental colleagues for proof-reading of the manuscript. E.P. Moiseeva’s work is funded by the grant PG /
99138 from British Heart Foundation.
[20]
[21]
[22]
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