See related article, pages 834 – 841
Physiological Smooth Muscle Cell Apoptosis Contributes to
the Uterine Vascular Remodeling in Human
Early Pregnancy
Jean-Jacques Helwig, Philippe Le Bouteiller
A
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doing to induce disorganization of the muscular layer of the
spiral arteries over the first trimester of pregnancy.4 They
based themselves on the idea that the loss of spiral muscular
layer is because of apoptosis of the VSMC, apoptosis most
likely triggered by a paracrine signal arising from trophoblasts. Besides the mitochondrial intrinsic pathway, the
membrane-bound death receptors of the tumor necrosis receptor family represent the major autocrine/paracrine or
extrinsic pathways that induce apoptosis in cells.2 The archetypal tumor necrosis receptor family death receptor is known
as the Fas receptor. This receptor binds its cognate ligand
FasL present in neighboring extracellular space, inducing
receptor trimerization and binding of the adapter protein
FADD (Fas Associated Death Domain) to the intracellular
part of Fas receptor. The Fas/FADD complex converts procaspase 8 into active caspase 8, which in turn activates other
downstream caspases, ultimately leading to DNA fragmentation
and cleavage of cellular proteins.5 In previous studies, the same
authors already made the interesting point that apoptosis triggered by the release of soluble FasL from invading trophoblasts
may contribute to the loss of both endothelial and VSMC from
the walls of spiral arteries during pregnancy.6 More recently,
other trophoblast-associated mechanisms have been evoked for
the induction of endothelial cell apoptosis in the utero-placental
environment. Thus, a major histocompatibility complex, the
so-called HLA-G1 complex has recently been proven to inhibit
angiogenesis through an apoptotic pathway by direct binding to
CD160 receptor expressed by activated endothelial cells.7
Tumor necrosis factor apoptosis inducing ligand (TRAIL)
is the more recently discovered second member of TNF
family ligand that is highly homologous to FasL and which,
like FasL, displays widespread expression throughout the
body, including endothelial and VSMC. As quoted by Koegh
et al, initial interest in TRAIL came from hope that TRAIL
could selectively induce apoptosis in cancer cells but not
in normal cells. The antitumorogenic properties of TRAIL
prompted the rapid identification of TRAIL receptors designated as TRAIL-R or DR (for death receptor). Unlike
TRAIL-R1 (DR4) and TRAIL-R2 (DR5), TRAIL-R3 and
TRAIL-R4 have no functional death domain which confers
minimal signaling capacity to these receptors. Because they
keep the ability to bind TRAIL they have been designated as
decoy receptors DcR1 and DcR2. TRAIL receptors DR4 and
DR5 and Fas have overlapping intrinsic signaling pathways,
in particular the ability to recruit FADD and to activate
pro-caspase 8. The interesting point here is that all these
receptors are widely expressed not only in malignant, but also
in normal cells. Moreover, unlike DR4 and DR5, DcR1 and
lthough equipped with the entire machinery driving
cell proliferation and cell death, the turnover of the
vascular smooth muscle cell (VSMC) layer within
the vascular wall is quite low throughout the adult normal
body. Vascular wall remodeling with VSMC apoptosis is
routinely considered as associated with vascular diseases.
This includes the development and regression of vascular
thickening in hypertension, in advanced atherosclerotic
plaques where VSMC apoptosis promotes plaque rupture,
after angioplasty-induced arterial injury, as well as in arterial
aneurysm where apoptosis is responsible for excessive slackening and rupture of the vessel media.1 Furthermore, in
several animal studies, early pregnancy is a physiological
situation where vessel wall remodeling plays a vital role.
Indeed, in the first trimester of human pregnancy, vascular
wall remodeling through degenerative changes converts the
uterine spiral arteries located within the decidua basilis into
toneless, widely opened arteries, thus enabling abundant
blood supply to the maternal-fetal exchange area within the
placenta. It is known that extravillous cytotrophoblasts deriving from fetal cytotrophoblastic shell migrate into segments
of the spiral artery wall, through retrograde endovascular
(intravasation) and interstitial migratory pathways (extravasation) into the decidua basilis to trigger the disappearance of
endothelial and VSMC. In this process, trophoblasts become
buried intramurally within a fibrinoid layer, which replaces
the original muscular medial layer. Such trophoblast invasion
converts the ends of spiral arteries into a wide caliber vessel
that can better deliver maternal blood to the expanding
intervillous space of the placenta (Figure 1A). Defective or
incomplete trophoblast invasion can result in pathological
pregnancies, including preeclampsia and intrauterine growth
restriction.2,3 Therefore, understanding the cellular mechanisms governing the interaction between intramural trophoblast and vascular wall cells is yet to be determined.
In this issue of Circulation Research, Keogh et al provide
important initial insight into what these trophoblastic cells are
The opinions expressed in this editorial are not necessarily those of the
editors or of the American Heart Association.
From the INSERM, Unit 727 (J.-J.H.), Strasbourg, France; Louis
Pasteur University, Strasbourg, France; INSERM, Unit 563 (P.L.B.),
Toulouse, France; Purpan Hospital, Toulouse, France.
Correspondence to Jean-Jacques Helwig, PhD, DrSci, Chief, INSERM
U727, ULP-Faculté de Médecine, 11 rue Humann-Bat.4-, 1eret, 67085
Strasbourg Cedex, France. E-mail jean-jacques.helwig@pharmaco-ulp.
u-strasbg.fr
(Circ Res. 2007;100:754-756.)
© 2007 American Heart Association, Inc.
Circulation Research is available at http://circres.ahajournals.org
DOI: 10.1161/01.RES.0000263394.59727.ca
754
Helwig and Le Bouteiller
Utero-Placental Vascular Smooth Muscle Apoptosis
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Oversimplified schematic depicting the trophoblasts invading
the spiral artery traveling from myometrium up to the decidua
basilis. A, The trophoblasts (green cells) originating from intervillous space invade the spiral artery wall via the interstitial or the
endovascular routes. In the spiral artery part which opens widely
on the intravillous space, the endovascular trophoblasts take the
place of the endothelium (yellow cells) and the intramural trophoblasts take the place of the VSMC (red cells).3 The bold red
arrow indicates the direction of blood flow. B, Koegh et al provide evidence that trophoblastic cells release TRAIL that bind to
VSMC trimeric death receptors 4 and 5 (DR4/5), which promotes recruitment of the adapter protein FADD. FADD, in turn,
allows binding and cleavage of procaspase 8 into activated
caspase 8. This triggers activation of the other members of the
caspase cascade which ultimately leads to VSMC death. In earlier studies, the same authors provided evidence for endothelial
cell (EC) death induced by trophoblast-derived FasL binding to
Fas on the EC (not shown).
DcR2 are unable to induce apoptosis but instead seem to
block it by trapping TRAIL.5
Koegh et al, are the first to establish a relationship between
fetal trophoblast-derived TRAIL and cell death in VSMC.4
Although VSMC have been proven to express Fas, the
specific question of whether they also express the TRAIL-Rs
has never been specifically addressed. Using flow cytometry
and immunohistochemistry, Koegh et al detected the expression of both DR4 and DR5 in VSMC of human aortic and
spiral artery VSMC. Exogenous TRAIL, either added to aortic
VSMC or perfused into denuded spiral artery segments induced
smooth muscle apoptosis, an effect proven to be mediated by
DR4 and DR5. Conversely, they found that extravillous trophoblasts isolated from first trimester placenta express TRAIL.
Impressively, in a video they also show direct contact between
trophoblast and aortic SMC, with typical blebbing of the VSMC
several hours after interaction between the cells. Also, a recombinant human DR4-Fc construct inhibits VSMC death induced
by the trophoblast. Taken together Keogh et al provide convincing evidence that TRAIL produced by trophoblast causes apoptosis of VSMC (Figure 1B).4 Thus, trophoblast-associated
remodeling of uterine spiral arteries during first trimester pregnancy may represent a unique example of physiological VSMC
apoptosis in normal adult human.
The aforementioned concept of decoy receptors for TRAIL
which can afford protection from TRAIL-mediated killing
raises the question of whether the decoy receptors DcR1 and
DcR2 are expressed in trophoblasts and how far this expression is modulated in spiral artery remodeling during early
755
pregnancy. Thus, referring to the studies in the field,5 it is
tempting to hypothesize that a putative decrease of the ratio
between DcR and DR expression in spiral VSMC during first
trimester pregnancy, attenuates the competition level for the
binding to TRAIL, which in turn facilitates medial disruption
by trophoblast-derived TRAIL. However, DcR regulation in a
physiological situation remains to be assessed. Future studies
examining the relative expression of DcRs and DRs in extravillous trophoblasts over the first trimester of pregnancy would
help in clarifying this question.
Although it is conceivable that trophoblasts indeed induce
spiral artery smooth muscle disorganization, it can be discussed the possible endovascular or interstitial origin of the
trophoblast invading the vascular wall in vivo and responsible
for the VSMC death. The endovascular route would imply
that trophoblast-associated endothelial cell apoptosis and
endothelium vacuolation would represent an initial crucial
step which leads to media disorganization. Such a situation
may occur deeper in the myometrial bed where interstitial
trophoblast are less dense, compared with the most decidua
basilis where intramural trophoblasts have better chance to be
derived from interstitial trophoblasts much more concentrated
in the decidual interstitium.2 Overall, these observations
prompt the controversial question as to whether endovascular
and interstitial become distinct trophoblast subtypes, taking
separate mechanistic pathways to contribute to the remodeling of spiral arteries. These questions require further
investigations.
In other respects, a link between DR4 and DR5 and the
status of the p53 tumor suppressor gene has also been extensively documented. It is now well accepted that this transcription factor controls critical steps in the cell cycle and mediates
cell apoptosis, not only through the mitochondrial pathway,
but also via a receptor-mediated pathway involving the DRs.
Moreover p53-response elements have been shown to be
present on the DR5 gene promoter. Finally events which
upregulate the DRs, like ␥ irradiation in spleen and small
intestine, have also been shown to be mediated by p53. Future
goals may involve the analysis of the p53 status in trophoblasts during early pregnancy.8,5
Another relevant question raised by the studies of Keogh et
al, is whether remodeling of spiral arteries depends entirely
on the action of trophoblasts or whether other cells might be
involved. In this context, the role of uterine natural killer cells
(uNK) has been questioned several times in animal studies
over the recent years. The hypothesis that uNK may be a
physiological actor of spiral artery remodeling has been
prompted by a series of observation, including an increased
number of uNK in the placental bed and the existence of
molecular interactions between uNK and the HLA-antigens
on the trophoblasts.2 As a summary, two major possible roles
of uNK in spiral artery remodeling have been proposed. In the
first proposition, uNK directly acts on vascular smooth
muscle remodeling. This assumption is strongly supported by
the absence of smooth muscle layer remodeling in NK-deficient
mice, in contrast to normal control animals.9 Interferon-␥ appeared to be the key cytokine produced by murine uNK and
participating in the spiral artery modifications.10 Besides the
direct action of uNK cells on spiral artery smooth muscle, it
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March 30, 2007
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has also been suggested that uNK cells control spiral artery
remodeling by controlling the trophoblast invasion. In support to this, it has recently been demonstrated that human
decidual NK cells, but not circulating NK cells, control
trophoblast invasion through the release of cytokine IL-8
and chemokine interferon-inducible protein 10 that bind to
receptors expressed on invasive extravillous cytotrophoblasts
and stromal cells present in the decidua basilis.11,12 Overall an array of previous findings show that uterine NK cells
have beneficial effects in early pregnancy instead of being
detrimental.
Functional studies of TRAIL system and its potency in
triggering spiral artery smooth muscle apoptosis in preeclamptic women should be useful in determining whether
DRs in these cells can be considered as potential therapeutic
targets. Apoptosis in VSMC has essentially been described as
being involved in most vascular diseases. But as Keogh et al
make clear in this issue of Circulation Research, physiologic
VSMC apoptosis also takes part in regulating the reproductive process.
Sources of Funding
The publication costs of this editorial are supported by the Institut
National de la Santé et de la Recherche Médicale, France. The
authors are financially supported by the Institut National de la Santé
et de la Recherche Médicale, France (J.J.H., P.L.B.), the University
Louis Pasteur Medical School, Strasbourg, France (J.J.H.), the
University Paul Sabatier, Toulouse, France (P.L.B.), and the European Union Network of Excellence EMBIC (Control of Embryo
Implantation) (P.L.B.)
Disclosure
None.
References
1. McCarthy NJ, Bennett M. The regulation of vascular smooth muscle cell
apoptosis. Cardiovasc Res. 2000;45:747–755.
2. Pijnenborg R, Vercruysse L, Hanssens M. The uterine spiral artery in
human pregnancy: facts and controversies. Placenta. 2006;27:939 –958.
3. Redman CW, Sargent IL. Latest advances in understanding preeclampsia.
Scienc. 2005;308:1592–1594.
4. Keogh RJ, Harris LK, Freeman A, Baker PN, Aplin JD, Withley GStJ,
Cartwright JE. Fetal-derived trophoblast utilize the apoptotic cytokine
TNF-␣–related apoptosis-inducing ligand to induce smooth muscle cell
death. Circ Res. 2007;100:834 – 841.
5. Kimberley FC, Screaton GR. Following a TRAIL: update on a ligand and
its five receptors. Cell Research. 2004;14:359 –372.
6. Ashton SV, Whitley GStJ, Dash PR, Wareing M, Crocker IP, Baker PN,
Cartwright JE. Uterine spiral artery remodelling involves endothelial
apoptosis induced by extravillous trophoblasts through Fas/FasL interactions. Arterioscler Thromb Vasc Biol. 2005;25:102–108.
7. Fons P, Chabot S, Cartwright JE, Lenfant F, L’Faqihi F, Giustiniani J,
Herault JP, Gueguen G, Bono F, Savi P, Aguerre-Girr M, Fournel S,
Malecaze F, Bensussan A, Plouët J, Le Bouteiller P. Soluble HLA-G1
inhibits angiogenesis through an apoptotic pathway and by direct binding
to CD160 receptor expressed by endothelial cells. Blood. 2006;108:
2608 –2615.
8. Burns TF, Bernhard EJ, El-Deiry WS. Tissue-specific expression of p53
target genes suggests a key role for KILLER/DR5in p53-dependent apoptosis in vivo. Oncogene. 2001;20:4601– 4612.
9. Croy BA, Esadeg S, Chantakru S, van den Heuvel M, Paffaro VA, He H,
Black GP, Ashkar AA, Kiso Y, Zhang J. Update on pathways regulating
the activation of uterine Natural Killer cells, their interactions with
decidual spiral arteries and homing of their precursors to the uterus.
J Reprod Immunol. 2003;59:175–191.
10. Ashkar AA, Di Santo JP, Croy BA. Interferon gamma contributes to
initiation of uterine vascular modification, decidual integrity, and uterine
natural killer cell maturation during normal murine pregnancy. J Exp
Med. 2000;192:259 –270.
11. Hanna J, Goldman-Wohl D, Hamani Y, Avraham I, Greenfield C,
Natanson-Yaron S, Prus D, Cohen-Daniel L, Arnon TI, Manaster I, Gazit
R, Yutkin V, Benharroch D, Porgador A, Keshet E, Yagel S, Mandelboim
O. Decidual NK cells regulate key developmental processes at the human
fetal-maternal interface. Nat Med. 2006;12:1065–1074.
12. Le Bouteiller P, Tabiasco J. Killers becomes builders during pregancy.
Nat Med. 2006;12:991–992.
KEY WORDS: spiral artery
䡲
placenta
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death receptors
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TRAIL
Physiological Smooth Muscle Cell Apoptosis Contributes to the Uterine Vascular
Remodeling in Human Early Pregnancy
Jean-Jacques Helwig and Philippe Le Bouteiller
Downloaded from http://circres.ahajournals.org/ by guest on June 17, 2017
Circ Res. 2007;100:754-756
doi: 10.1161/01.RES.0000263394.59727.ca
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