Vascular remodelling and extracellular matrix breakdown in the uterine spiral arteries
during pregnancy
Harris, LK and Aplin, JD
Division of Human Development
Faculty of Medical and Human Sciences
University of Manchester
UK
Correspondence: Room 74, Research Floor, St Mary’s Hospital, Manchester M13 0JH, UK
Email: [email protected], Tel: (44) 161 2766487
Key words: artery, trophoblast, decidua, myometrium, invasion, extracellular matrix, proteolysis,
elastin, apoptosis, vascular smooth muscle
Running head: Spiral artery remodelling in pregnancy
Abstract
During pregnancy, trophoblast invades and transforms the maternal spiral arteries that supply
blood to the placenta. Recent work has revealed that this process occurs in several stages, and
details of the molecular and cellular mechanisms are beginning to emerge, including changes that
precede or accompany trophoblastic colonisation of the vascular media. Disruption and eventual
loss of smooth muscle cells and their associated extracellular matrix are central to physiological
transformation. Advances in understanding will lead to the identification of the causative factors
involved in failure of remodelling in pathological pregnancies, and suggest novel diagnostic and
therapeutic avenues.
Introduction
Remodelling of the uterine spiral arteries during the first twenty weeks of gestation is crucial for
a successful outcome of pregnancy. During this process, these narrow, muscular, highly coiled
vessels are widened to form high flow, low resistance channels that lack vasomotor control. This
radical change in vessel architecture involves the loss of endothelial cells (EC) and smooth
muscle cells (SMC), and degradation of elastin fibres within the internal elastic lamina and
musculo-elastic media. Vascular cells are replaced by trophoblasts, derived from the developing
placenta, embedded in an amorphous fibrinoid matrix. Little is known about the properties of this
material; however, the combination of trophoblast embedded in fibrinoid allows the spiral arteries
to maintain their integrity in the absence of elastic tissue.
The purpose of spiral artery remodelling is to ensure that an adequate volume of blood is directed
to the intervillous space, at a low enough pressure as not to damage the placental villi. This
process is initiated under maternal control prior to trophoblast invasion
1
but complete
physiological transformation requires the mediation of extravillous trophoblasts, which detach
from anchoring placental villi and invade the uterine wall (interstitial invasion) or migrate in a
retrograde manner through the lumen of the spiral arteries as far as the first third of the
myometrium (endovascular invasion)
2, 3
. It is the interactions of these two distinct trophoblast
populations with the spiral arteries that results in specific changes to vessel wall structure.
Incomplete remodelling of spiral arteries is associated with second trimester miscarriage 4,
preterm labour 5, and pregnancy complications such as pre-eclampsia and some cases of fetal
growth restriction (FGR) 3. These conditions are characterised by shallow trophoblast invasion, a
decreased population of invasive trophoblast and narrow bore arteries retaining muscular walls,
further implicating trophoblast invasion as essential to the remodelling process.
Extracellular matrix in the vasculature
The structure and function of the arterial wall is dependent on its resident cells together with the
extracellular matrix (ECM), which provides scaffolding and structural support. The ECM is a
complex assembly of macromolecules, each with unique biomechanical properties, that act in
combination to confer arteries with mechanical strength, elasticity, resilience and compressibility.
ECM components found in vessels walls include collagen, glycoproteins, proteoglycans and
elastic fibres, which are synthesised by EC and SMC. Pericytes, the mesenchymal-like cells that
associate with the walls of small blood vessels, also produce ECM components, including
basement membrane matrix proteins, proteoglycans such as decorin, biglycan, versican, and
aggrecan, fibronectin and various collagens. 6-9
ECM components
Collagen is one of the major components of resistance arteries, providing physical and tensile
strength and limiting vessel distension. There are 42 collagen genes in the human genome
encoding 27 collagen types 10; types I, III and V are present in large banded fibrils in the intima,
media and adventitia. Collagen IV forms a scaffold in the basement membrane of EC and SMC.
11
. Collagen VI microfibrils are also observed. Collagen VIII, XII, XIV and XVIII make up less
than 10% of the total collagen present.12 Elastin is the other main constituent of the vascular
ECM, conferring support, deformability and passive recoil. These properties allow arteries to
regulate changes in blood pressure, which is essential to maintain a constant blood flow. Mature
elastic fibres are practically insoluble and metabolically inert, and are comprised of a
homogenous elastin core that is assembled along a scaffold of parallel microfibrils. Elastin is
comprised of a polymer of tropoelastin molecules which, in arteries, are mainly synthesized by
SMC. The microfibrils are made up of different glycoprotein constituents, including fibrillin-1
and -2, microfibril-associated glycoproteins (MAGP-1 and -2) and latent transforming growth
factor-β (TGF-β)-binding proteins. These fibres interact with chondroitin sulphate proteoglycans
and proteins localised to the elastin–microfibril interface or to the cell surface–elastic fibre
interface, called elastin microfibril interface-located proteins (EMILIN). EMILIN-1 may play an
important role in anchoring cells to elastic lamellae, as elastic fibres in the EMILIN-1 knockout
mouse exhibit alterations in structure, leading to loss of connections between the elastic lamellae
and vascular cells.13 Interestingly, EMILIN-1 is expressed by stromal and muscle cells in the
uterus
14
, and a gradient of EMILIN-1 expression has been noted in the perivascular region of
some transformed spiral arteries. Thus, this molecule may promote haptotactic migration of
interstitial trophoblasts.
Other ECM molecules found in the arterial wall include laminin, the most abundant glycoprotein
in basement membranes. It acts as a linker, binding to cells, heparan sulphate proteoglycan and
collagen IV. Fibronectin, another multifunctional ECM protein, bridges between cell surface
integrins and the ECM, thus mediating cell-matrix adhesion. It is synthesised by fibroblasts,
monocytes, SMC and EC, and binds to collagen, fibrin, and proteoglycans. Proteoglycans are
present within the arterial intima and media, and are synthesised by SMC, other mesenchymal
cells and by EC in the basement membrane. These are highly disperse, hydrated molecules,
formed from different combinations of core proteins and glycosaminoglycans (GAGs). They
possess a net negative charge, and mediate selective filtering in the basement membrane. The
GAG hyaluronan is found within the intima, where it binds large amounts of water to form a
viscous hydrated gel which provides the vessel wall with turgor, resilience and lubrication. It is
synthesised primarily by SMC and serves as a ligand for core proteins, and a backbone for large
proteoglycan complexes.
Extracellular matrix breakdown
Catabolism and reorganisation of the ECM is fundamental for successful mural remodelling.
Poiseuille's law, which relates laminar flow and vascular resistance to the radius of a vessel,
states that a small increase in the diameter of the spiral arteries results in a marked decrease in
resistance and/or an increase in blood flow. Alterations in composition or spatial arrangement of
matrix components within the arterial wall can impact on vessel function, leading to loss of
vascular tone and vasomotor control. Thus, the actions of the trophoblast which facilitate vascular
cell loss and ECM degradation mediate a decrease in blood pressure and enhanced blood flow
within the intervillous space. To invade the walls of the spiral arteries, endovascular trophoblasts
must penetrate the endothelial cell layer and traverse the basement membrane. In myometrial
vessels, they must then degrade the internal elastic lamina before reaching the underlying medial
SMC. In decidual vessels, the internal elastic lamina is absent, however, trophoblasts are still
required to break down the elastin fibres that reside between layers of smooth muscle. They may
also need to degrade medial proteoglycans including decorin, versican and perlecan. Interstitial
trophoblasts colonising vessels from the outside must degrade collagen and elastin within the
adventitia before reaching the arterial media.
Because of the complex composition of vascular ECM, trophoblasts require a plethora of
proteases to invade the vessel wall. These include the matrix metalloproteases (MMPs), a
disintegrin and metalloprotease domains (ADAMs), cathepsins, caspases, and serine proteases
such as urokinase plasminogen activator (uPA), chymotrypsin, trypsin and elastase. Endovascular
trophoblasts migrating transluminally through the spiral arteries, adhere to the endothelium and
penetrate the intimal layer via cell-cell junctions. They must then traverse the basement
membrane upon which the EC reside. This is an amorphous layer containing type IV collagen,
laminin and perlecan. Several different MMPs have been shown to degrade basement membrane
matrix components, including MMP-3, MMP-9, MMP-10 and the membrane associated MTMMPs.
15-18
In addition, MMP-3, MMP-7
19
, the MT-MMPs,
20
and ADAM-10 and -15
21, 22
facilitate the disassembly of contacts at EC–EC junctions; these interactions are key for
maintaining intimal integrity in normal vessels,
23, 24
so their breakdown is a prerequisite for
trophoblast intravasation. Of the proteases listed above, isolated first trimester trophoblasts or
extravillous trophoblasts in situ are known to produce MMP-1, -2, -9 -12 and MT1-MMP
25-29
.
The endothelium itself may also control the elastic properties of the arterial wall, 30, 31 thus loss of
EC or disruption of the intimal layer may contribute to an increase in the diameter of the spiral
arteries.
Elastic fibres
Breakdown of elastin within the internal elastic lamina and the vessel media is crucial to allow
expansion and abolish elastic recoil. Catabolism of elastic fibres not only impairs the mechanical
performance of the arterial wall, but also removes the physical barrier that immobilises SMC and
prevents their migration and proliferation. In mature blood vessels, SMC possess a contractile
phenotype and exhibit a very low rate of proliferation and synthetic activity, however, they retain
a phenotypic plasticity which allows them to carry out reparative processes after injury. In most
vessels, damage to the intima stimulates SMC to adopt a proliferative, synthetic phenotype. If
breaks in the internal elastic lamina are present, SMC may migrate into the lumen, leading to
proliferation, neointima formation and arterial narrowing. The interstitial-type ECM components
fibronectin and type I, III and V collagen promote transition of SMC to a synthetic phenotype in
vitro, whereas SMC cultured on basement membrane or elastic lamina-type ECM components
such as laminin, type IV collagen, elastin, heparin, or heparan sulphate retain a contractile
phenotype.32 Hence, regulated degradation of basement membranes or elastic laminae by invasive
trophoblast may promote dedifferentiation of overlying SMC, either via the release of bioactive
ECM fragments or as the underlying interstitial ECM is exposed. There is also evidence that
trophoblasts release signals that trigger SMC death 33, 34.
Elastin-derived peptides
High systolic and pulse pressures caused by advanced age or hypertension have been shown to
increase the level of circumferential stress on the walls of arteries and lead to breakdown of
elastic fibres.35 We hypothesise that high pressure in the myometrial spiral arteries, generated by
trophoblast plugs in the proximal vessel segments, may contribute to elastin breakdown by
creating initial fractures in the internal elastic lamina through which trophoblasts may pass. Many
vascular diseases are characterised by breakdown of elastin and release of elastin degradation
products termed elastin-derived peptides (EDP). EDP exhibit a wide range of biological activities
and may have an important role to play in the regulation of tissue remodelling. Generation of
EDP by macrophage-derived MMP-12 has shown to be important in the development of a murine
model of emphysema.36 In this system, pulmonary macrophages degrade elastin to generate
EDP, which are chemotactic for monocytes. This leads to recruitment of further leukocytes to the
lung, release of more EDP and a gradual worsening of the condition. EDP can also stimulate
chemotaxis and chemokinesis of leukocytes into the walls of damaged arteries, where they
contribute to matrix breakdown and repair.37 We hypothesise that EDP generated following
trophoblast invasion of the spiral arteries may contribute to the recruitment of leukocytes to the
vessel wall.
EDP have also been shown to stimulate quiescent arterial SMC to adopt a more proliferative
phenotype.38-41 When aortic SMC are cultured with EDP, they upregulate production of
fibronectin which promotes this phenotypic switch.42 Furthermore, EDP upregulates MMP
expression in a variety of cancer cell lines, including human fibrosarcoma HT-1080 cells, breast
and melanoma cell lines, promoting both migration and invasion.
43-45
As MMP can themselves
cleave elastin, the actions of EDP not only facilitate cell migration and invasion, but also
establish a positive feedback mechanism by which EDP production is maintained. We have
observed that trophoblast can degrade insoluble elastin fibres in vitro, generating smaller elastin
fragments. The intracellular elastase activity of vascular SMC is increased following culture with
elastin fragments. Furthermore, MMP activity in SMC is increased upon treatment with
trophoblast conditioned medium, both in vitro and in perfused spiral artery segments (LKH and
JDA, unpubished). These findings suggest that soluble factors produced by trophoblasts, and
elastin fragments generated following trophoblast invasion, may stimulate elastase production in
vascular SMC in vivo. We therefore hypothesise that the actions of invasive trophoblasts
potentiate elastin breakdown by SMC during arterial remodelling.
Along with the local generation of EDP in vascular disease, evidence of the breakdown of other
ECM constituents can be detected in the plasma following an acute coronary event. Elevated
levels of collagen propeptides (PIIINP),
(PICP)46,
48, 49
46, 47
and the C-terminal propeptide of procollagen I
persist within the circulation for several weeks. Endostatin, derived from the C-
terminal fragment of the 1-chain of type XVIII collagen, can be detected in plasma following
remodelling events. Endostatin is liberated via cleavage of a protein-sensitive hinge, by cathepsin
L, matrilysin (MMP-7) and elastase. This molecule has potent anti-angiogenic effects and
induces growth arrest and apoptosis of endothelial cells. It can also stabilise cell-cell and cellmatrix interactions, inhibit MMP-2 activity and antagonise binding of several vascular
endothelial growth factor (VEGF) isoforms to the receptor Flk-1
50
. Local release of endostatin
from the vessel wall during spiral artery remodelling may therefore promote EC loss. We
hypothesise that markers of matrix breakdown may be evident within the blood during the first
twenty weeks of pregnancy, as the spiral arteries are remodelled. It may be interesting to
ascertain whether a “plasma profile” of matrix fragments is evident in pregnant women, and
whether changes in this profile could be used to identify women with impaired arterial
remodelling.
Candidate elastases
Human proteases capable of degrading elastin include MMP-2, MMP-3, MMP-7 MMP-9, MMP12, MMP-13,51,
52
neutrophil elastase, trypsin, chymotrypsin53 and SMC elastase/endogenous
vascular elastase (EVE),54 as well as caspase-2, -3 and -7 55 and the cathepsins B, K, L and S.56 In
the vascular wall, the majority of elastases are secreted from activated SMC, 57 although they are
also produced by neutrophils,58 macrophages59 platelets60 and EC.61 Trophoblast are known to
produce several elastases including MMP-2, -7 and -9, and cathepsins B and L. 62, 63 Interestingly,
the elastase precursor pro-MMP-2 can be activated by elastin itself. Upon binding to insoluble
elastin via its collagen binding domain, pro-MMP-2 is completely converted into its active form,
in the absence of other proteolytic activators.64 However, in healthy vessels, pro-MMP-2 is
constitutively expressed in the arterial wall, and no elastin breakdown is detectable.12
In common with spiral arteries, studies of human arteries containing atherosclerotic lesions have
shown that protease expression is upregulated in vascular SMC during the process of vessel
remodelling. SMC-derived cathepsin S and K have been found to localise to breaks in the internal
elastic lamina within atherosclerotic lesions, whereas normal vessels show little or no cathepsin
expression.65 Macrophages within atherosclerotic lesions also express proteases, including MMP14 which co-localises with MMP-2, MT3-MMP (MMP-16)66 and neutrophil elastase67. As
macrophages constitute approximately twenty percent of the immune cells of the decidua,
macrophage-derived proteases may have a role to play in spiral artery remodelling. However,
their presence is inversely correlated with successful vessel remodelling,68 so it is likely that this
is not their major role in vivo. Uterine NK cells constitute around 70% of the decidual leukocyte
population during the first twenty weeks of gestation, after which time their numbers begin to
decline. These cells play an essential role in the initiation of decidual artery remodelling in the
mouse
69
, however less is known about their role in humans. Uterine NK cells may indirectly
modulate matrix breakdown as it has previously been shown that uNK cell-derived interferon-
upregulates genes in the decidual stroma that limit trophoblast invasion in mice 70, and interferon decreases the invasion of human extravillous trophoblast cultures via a reduction in MMP-2
activity 27. Mast cells are present in low numbers within the placental bed, in association with the
spiral arteries, and mast cell chymase can degrade fibronectin
71
and type I procollagen.72
However, these cells are unlikely to play a significant role in regulating connective tissue
homeostasis, as increased numbers of mast cells are associated with abnormal, rather than healthy
pregnancies. 73-75
Growth factors
As well as facilitating transit through the vessel wall, MMPs can also liberate growth factors that
are stored in the extracellular matrix, including TGF- and VEGF. MMP-9 releases VEGF bound
to proteoglycans, MMP-2 can release TGF- bound to the ECM, and MMP-2, -9, -13 and -14 can
all activate TGF-.17 uPA may also promote growth factor release 76. The availability of growth
factor may enhance the survival of invading trophoblasts; conversely, depletion of such factors
may promote apoptosis of SMC. In addition, stimulation of signalling pathways following growth
factor release may alter cell behaviour in a manner that promotes remodelling.
Conclusion
Remodelling of the uterine spiral arteries is a highly complex process, effected in part by
trophoblasts and trophoblast-derived proteases. To maintain vascular integrity, loss of vascular
cells and breakdown of ECM must be carefully co-ordinated and slowly implemented over the
first twenty weeks of gestation. It is clear that other cell types, such as macrophages, uNK cells
and mast cells are present in the environs of the spiral arteries, and have the capacity to degrade
ECM. Whether they play a direct role in matrix breakdown is yet to be established. Preliminary
results from our laboratory show that spiral artery SMC alter their protease profile in response to
trophoblast invasion and free elastin fragments, and may contribute to breakdown of ECM
components within the arterial wall.. Though much work is needed before a complete picture
emerges of the molecular mechanisms of arterial remodelling, avenues for developing diagnostic
tests and targets for therapeutic interventions are starting to become evident.
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