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Please cite this article in press as: Blois, S.M., et al., Decidualization and angiogenesis in early pregnancy: unravelling the

functions of DC and NK cells. J. Reprod. Immunol. (2011), doi:10.1016/j.jri.2010.11.002

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Journal of Reproductive Immunology xxx (2010) xxx–xxx

Contents lists available at ScienceDirect

Journal of Reproductive Immunology

j o u r n a l h o m e p a g e : w w w . e l s e v i e r . c o m / l o c a t e / j r e p r i m m

Decidualization and angiogenesis in early pregnancy: unravelling thefunctions of DC and NK cells

Sandra M. Blois ∗, Burghard F. Klapp, Gabriela Barrientos

Charité Centrum 12 für Innere Medizin und Dermatologie, Reproductive Immunology Research Group, University Medicine of Berlin, Germany

a r t i c l e i n f o

Article history:

Received 1 September 2010

Received in revised form 29 October 2010

Accepted 4 November 2010

Available online xxx

Keywords:

Dendritic cells

NK cells

Decidualization

Decidual angiogenesis

Implantation

a b s t r a c t

Differentiation of endometrial stromal cells and formation of new maternal blood vessels

at the time of embryo implantation are critical for the establishment and maintenance of

gestation. The regulatory functions of decidual leukocytes during early pregnancy, partic-

ularly dendritic cells (DC) and NK cells, may be important not only for the generation of

maternal immunological tolerance but also in the regulation of stromal cell differentiation

and the vascular responses associated with the implantation process. However, the specific

contributions of DC and NK cells duringimplantation arestill difficult to dissect mainly due

to reciprocal regulatory interactions established between them within the decidualizing

microenvironment. The present review article discussescurrent evidence on the regulatory

pathways drivingdecidualization in mice, suggesting thatNK cells promoteuterinevascular

modifications that assist decidual growth but DC directly control stromal cell proliferation,

angiogenesis and the homing and maturation of NK cell precursors in the pregnant uterus.

Thus, successful implantation appears to result from an interplay between cellular compo-

nents of the decidualizing endometrium involving immunoregulatory and pro-angiogenicfunctions of DC and NK cells.

© 2010 Published by Elsevier Ireland Ltd.

1. Introduction

In mice, the implantation of a blastocyst into the uterus

initiates a transformation process, known as decidualiza-

tion, and creation of an extensive vascular network within

thestromal bed, leading to the establishment of pregnancy.

Despite some differences among species, the onset of

implantation always involves complex regulatory mecha-nisms operating on the uterine lining to make it competent

for blastocyst attachment. The steroid hormones, estrogen

and progesterone play a central role during this process,

driving a series of cellular and molecular interactionsin the

∗ Corresponding author at: Charité Centrum 12 für Innere Medizin

und Dermatologie, Reproductive Immunology Research Group, Univer-

sity Medicine of Berlin, BMFZ-Raum 2.0547, Campus Virchow Klinikum,

Augustenburger Platz 1, 13353 Berlin, Germany. Tel.: +4930 450 553791,

fax: +49 30 450 553962.

E-mail address: [email protected](S.M. Blois).

underlying endometrial stroma to form thedecidua, a tran- 28

sient tissue that supports embryo growth and maintains 29

early pregnancy (Dey et al., 2004). 30

Accumulating evidence suggests that immune cells are 31

an important regulatory component within the uterine 32

milieu during early pregnancyin mice. Decidual leukocytes 33

have been extensively characterized with the initial aim of 34

gaining a clear understanding of the regulation of mater- 35

nal tolerance towards fetal alloantigens (Blois et al., 2007), 36

but may also exert regulatory functions during early preg- 37

nancy that go beyond their classical roles as components 38

of the immune system. In particular, recent studies have 39

highlighted the importance of DC (Krey et al., 2008; Plaks 40

et al., 2008) and NK cells (Croy et al., 2003a; Hanna et al., 41

2006) in the regulation of stromal cell differentiation and 42

the vascular responses associated with the implantation 43

process. The intimate contact observed between DC and 44

NK cells, which are often found in the vicinity of decidual 45

blood vessels (Blois et al., 2008; Kammerer et al., 2003), 46

0165-0378/$ – see front matter © 2010 Published by Elsevier Ireland Ltd.doi:10.1016/j.jri.2010.11.002

http://dx.doi.org/10.1016/j.jri.2010.11.002



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2 S.M. Blois et al. / Journal of Reproductive Immunology xxx (2010) xxx–xxx

suggests that reciprocal interactions between them may7

also be important in shaping the decidualizing microen-8

vironment during early pregnancy. The first insights have9

been provided by in vitro studies showing that the prolif-0

eration of uterine cells is highly dependent on a synergistic

effect of DC and NKcells(Blois et al., 2008), suggesting that2

such DC-NK cell cross-talk may be important in driving the3

differentiation of the endometrial stroma during implanta-4

tion. In turn, DC appear to play a pivotal role in promoting5

the differentiation of uterine NK (uNK) cells, as highlighted6

by recent in vivo studies describing impaired NK cell func-7

tions in association with decreased levelsof IL-15 and IL-128

in DC depleted implantationsites(Karsten et al., 2009; Krey9

et al., 2008).0

The decidua serves a variety of functions including

the production of growth factors and cytokines to sustain2

embryo development, the regulation of maternal immune3

responses and the control of trophoblast invasion into the4

uterus. The timely coordination of the endometrial changes5

occurring during decidualization is thus critical for the6

establishment of pregnancy, and the elucidation of the cel-7

lular and molecular mechanisms involved may greatly aid8

the design of new therapeutic approaches to pregnancy9

failure. While the morphological changes occurring in the0

endometrialstroma and the hormonal pathways regulating

them are well described aspects that define the decidual-2

ization process, the above evidence points to an important3

role played by DC and NK cells that needs to be further4

explored. Thus, the present review article integrates our5

recent studies on uterine DC physiology with a discussion6

of current knowledge on regulatory pathways operating7

at the endometrium during early pregnancy. Particular8

emphasis will be given to thecontributions of DC to stromal9

cell proliferation and differentiation as the most promi-0

nent feature of the decidualization process, as well as their

interplay with the NK cell subset in promoting vascular2

remodeling and angiogenesis associated with it.3

2. Implantation and decidualization4

Implantation is the process by which the blastocyst5

assumes a fixed position andestablishes an intimate physi-6

ological relationship with the uterine endometrium. Rather7

than a single event, implantation can be seen as a series8

of three stages (apposition, attachment and penetration)9

forming a continuum (Schlafke and Enders, 1975). Appo-0

sition denotes the first intimate contact of the blastocyst

with the endometrium, which in mice can be evidenced as2

a generalized stromal edema that precedes the closure of 3

theuterine lumen at gestationday (Gd)4.5. This is followed4

by increased vascular permeability at the implantation site5

and apoptosis of the epithelial cells during the attachment6

reaction, resulting in a closer contact and the subsequent7

penetration through the endometrial stroma in a regulated8

manner (Dey et al., 2004).9

Blastocyst attachment always occurs in the antime-0

sometrial side of the mouse uterus and triggers the

proliferation of the stromal cells adjacent to the implan-2

tation site, initiating a unique cell differentiation process3

known as decidualization. By Gd 5.5, the stromal cells4

immediately surrounding the embryo differentiate to form5

a primary decidual zone (PDZ) while cell proliferation con- 106

tinues towards the mesometrial compartment, eventually 107

establishing a secondary decidual zone (SDZ) representa- 108

tive of the terminal differentiation of the decidual tissue at 109

Gd 7.5 (Dey et al., 2004). Though the normal stimulus for 110

decidualization is the attachment reaction, certain agents 111

(i.e., oil) can induce a similar process (resulting in decid- 112

uoma formation) when applied locally to pseudopregnant 113

or hormonally treated mice (Hirabayashi et al., 1999; Paria 114

et al., 2001). 115

Regardlessof the initiatingstimulusinvolved, the decid- 116

ualization process is always associated with extensive 117

proliferation and differentiation in the stromal compart- 118

ment, rendering large decidual cells often with binucleated 119

or polyploid status. This is the result of an atypical cell 120

cycle driving DNA replication without cell division, which 121

is tightly regulated through a complex interplay of cyclins, 122

cyclin-dependent kinases (CDKs) and their inhibitors as 123

the classical mediators controlling cell cycle progression 124

in mammalian cells. In mice, cyclin D3 expression at the 125

implantation sitehas been associatedwith the proliferation 126

of decidualizing stromal cells, probably through functional 127

association with cdk4 (Das et al., 1999; Tan et al., 2002). 128

Later on, persistent cyclin D3 expression concomitant with 129

a switch from cdk4 to cdk6 expression and the induction 130

of the p21 inhibitor is thought to drive the terminal differ- 131

entiation of the endometrial stroma. The involvement of 132

cell cycle regulatory proteins in this process is further sup- 133

ported by the finding that the expression of several of these 134

molecules (i.e., cyclin D3 and p21) in the decidua depends 135

on IL-11, a cytokine that has been found to be indispens- 136

able for normal decidualization (Li et al., 2008; Robb et al., 137

1998). 138

It is still difficult to determine the physiological role 139

played by stromal cell polyploidy during the decidualiza- 140

tion process. One of the many functions of the decidua 141

is to support embryo growth during early pregnancy and 142

in this context, polyploidy may increase the biosynthetic 143

capacity of decidual cells by increasing the number of gene 144

copies for transcription. Polyploidization eventually leads 145

to apoptosis of the differentiating cells and may therefore 146

be implicated in the transient nature of the decidual tis- 147

sue, limiting the life span of these cells to allow placental 148

expansion and development (Dey et al., 2004). 149

2.1. Uterine NK cells and decidualization: what comes 150

first? 151

Uterine NK cells are probably the best studied leukocyte 152

population in the mouse and human decidua. In contrast to 153

the human endometrium, where these cells emerge post- 154

ovulation, mature NK cells do not appear in the mouse 155

uterus prior to implantation (King, 2000). Decidual IL-15 156

drivesthe maturation of NK cell precursors into large, gran- 157

ulated cells that gradually accumulate in the mesometrial 158

compartment and start producing detectable levels of IFN 159

at Gd 6.5 (Ashkar et al., 2003; Croy et al., 2003b). 160

Although they differ in the dynamics of their recruit- 161

ment, human and mouse uNK cells are the most abundant 162

leukocyte subset at the time of decidualization and are 163

therefore likely to influence this process. Indeed, uNK cell 164







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deficiency in mice has often been associated with decid-

ual growth defects including hypocellularity, necrosis and

edema (Ashkar et al., 2000, 2003; Guimond et al., 1997).

Besides recent in vitro studies showing that uNK cell-

derived factors can influence the gene expression profile

of human endometrial fibroblasts (Germeyer et al., 2009),

evidence to support a direct effect exerted by uNK cells

on stromal cell differentiation is still largely elusive. In

mice, the major defects associated with a lack of uNK cell

signaling during early pregnancy are in fact observed in

the decidual vasculature, showing undilated spiral arteries

that retain their smooth muscle coats throughout gestation

(Ashkar et al., 2000). Thus, a possible scenario is that rather

than directly affecting the differentiation of stromal cells,

the main contribution of uNK cells may be to induce vascu-

lar changes that ensure an adequate blood flow to sustain

tissue growth during the decidualization process.

Vascular modifications induced by uNK cells may gain

particular importance as gestation advances in promoting

placental development. Indeed, implantation in mice pro-

gresses normally in theabsence of uNKcellsand fetal loss is

not detected prior to Gd 10.5 in association with an abnor-

mal architecture of the placental tissues (Guimond et al.,

1997). Gene knock-out modelshave recently demonstrated

that many molecules originally associated with infertil-

ity due to implantation and decidualization failure (i.e.,

IL-11 and homeobox A10) can also affect the recruitment

and maturation of NK cells in the uterus (Ain et al., 2004;

Rahmanet al., 2006). In thiscontext, the earlyaccumulation

of uNK cells should not be seen as a mechanism promot-

ing decidualization but as one of the many endometrial

changes that occur during this process to support normal

pregnancy progression.

The above evidence strongly supports an association

between NK cell functions and the endometrial changes

occurring during early pregnancy, but raises many ques-

tions as to their specific contributions to the different

aspects involved in thisprocess. While vascular remodeling

and development within the decidual bed is most likely to

be regulated by uNK cell derived signals, their direct effects

on endometrial stromal cells are less evident but cannot be

precluded. Therefore, ongoing research in our lab aims at

characterizing uNK cell effects on stromal cell differentia-

tion to provide further insights into the input of this subset

on endometrial decidualization during the early stages of

pregnancy.

2.2. Uterine conventional DC: upstream regulators of

stromal cell differentiation

Resembling other mucosal surfaces, the decidua is

enriched with MHC class II+ antigen presenting cells rep-

resenting more than 10% of the leukocyte population (Blois

et al., 2004; Kammerer, 2005). The most prominentof these

are CD11c+ DC, which have been extensively character-

ized in mice and humans in terms of their potential to

induce immune tolerance during pregnancy (Blois et al.,

2007; Kammerer et al., 2008). DC become most abundant

in the mouse uterus at Gd 5.5, where this early accumula-

tion has been linked to the transient inflammatory milieu

characteristic of the implantation window (Blois et al.,

Fig.1. Schematic representation showinga putativenetworkof DCNKcell

interactions during the early stages of pregnancy. DC directly modulate

the proliferation and differentiation of stromal cells and the angiogenic

expansionof the endometrialvascularbed to sustaintissue growth during

decidualization. DC-derived IL-15 would promote the recruitment andmaturation of NK cell precursors that in turn cooperate in the regulation

of vascular development and remodeling through the production of pro-

angiogenic (e.g. VEGF) and vasoactive mediators.

2004). Besides theseclassicalimmunoregulatory functions, 224

recent studies suggest that DC are a pivotal component 225

of the embryo-maternal dialogue driving implantation by 226

directly influencing uterine receptivityand decidualization 227

(Fig. 1; Krey et al., 2008; Plaks et al., 2008). These stud- 228

ies demonstrated that the absence of DC from the mouse 229

uterus during the peri-implantation period results in early 230

pregnancy failure due to impairments in the decidualiza- 231

tion process including defective stromal cell proliferation, 232

abnormal differentiation of the mesometrial and antime- 233

sometrial compartments and reduced vascularization of 234

the implantation sites. Importantly, the defects associated 235

with DC depletion were also observed upon the induction 236

of deciduoma and in syngeneic pregnancies (Plaks et al., 237

2008), pointing to a key role of DC as promoters of stro- 238

mal cell differentiation that functions independently from 239

tolerance induction. 240

Experiments in vitro involving the co-culture of tro- 241

phoblasts with DC, NK cells and uterine cells isolated from 242

murine allogeneic pregnancies showed that trophoblasts 243

boosted the proliferation rate of uterine cells only when 244

cultured in the presence of both DC and NK cells (Blois 245

et al., 2008), providing the first insights into a role played 246

by DC in driving decidualization in cooperation with NK 247

cells. However, the interactions between DC and NK cells 248

underlying this requirement for both cell subsets in the 249

promotion of stromal cell proliferation await further char- 250

acterization. One possibility is thatthere exists a synergistic 251

effect involving direct actions on stromal cells mediated by 252

both DC and NK cells. Alternatively, this observation could 253

reflect a hierarchical event in which DC directly promote 254

stromal cell growth and differentiation during decidual- 255

ization and their physical interactions with NK cells within 256

the uterus would be involved in the regulation of this pro- 257

cess. In this regard, the selective depletion of DC in vivo 258

has also been associated with impairments in the recruit- 259







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mentandmaturationofuNKcells(Karsten et al., 2009; Krey0

et al., 2008), which could represent a self-directed con-

trol mechanism induced by DC during the decidualization2

process.3

Uterine DC do not differ from those found in other4

tissues in being a highly heterogeneous cell popula-5

tion (Kammerer et al., 2008). However, evidence on6

the contribution of different decidual DC subsets to the7

establishment of pregnancy remains largely elusive. The8

administration of diphtheria toxin (DT) to CD11c-DTR9

transgenic mice results in the selective elimination of 0

conventional DC (CD11chigh DC) ( Jung et al., 2002), but

spares plasmacytoid DC (pDC) because of their low lev-2

els of CD11c expression. Therefore, it can be assumed3

that the regulatory functions ascribed to DC during mouse4

endometrial decidualization do not rely on cells belong-5

ing to the plasmacytoid subset. Indeed, we corroborated6

this result using the 120G8 monoclonal antibody, which7

reacts with bone marrow stromal Ag-2 (BST-2) expressed8

by pDC, as an alternative approach to deplete this subset9

in vivo (Asselin-Paturel et al., 2003). We chose to assess0

not only the role of pDC during implantation (Gd 3.5),

but also in peri-implantation (Gd 7.5) and late pregnancy2

(Gd 11.5). As shown in Fig. 2, depletion of pDC neither3

affected pregnancy outcome nor the number of implanta-4

tion sites,suggesting that pDC arenot involved in anyof the5

mentioned processes during gestation in mice. However,6

it is important to note that pDC numbers were gradually7

restored after 48 h during the antibody-mediated deple-8

tion approach. Thus, the recently generated blood dendritic9

cell antigen-2 (BDCA-2)-DTR transgenic mouse (Swiecki0

and Colonna, 2010) represents a unique tool to further

investigate the role of pDC during gestation as repeated2

administration of DT does not appear to be lethal in this3

model, allowing long term depletion of these cells with4

high efficacy and specificity. In addition,further studies will5

be required to dissect the role of individual CD4+ or CD8+6

CD11chigh populations in implantation outcome as well as7

the underlying mechanisms involved.8

3. Angiogenesis and implantation9

The establishment of pregnancy is highly dependent on0

theproper coordinationof several vascular processesat the

maternal–fetal interface to ensure an adequate blood flow2

in response to the increasing metabolic demands of the3

embryo. Implantation and decidualization occur together4

with an extensive remodeling of the endometrial vascula-5

ture, during which vascular expansion through the process6

of angiogenesis plays a central role (Torry et al., 2007).7

Angiogenesis is a rare phenomenon in most adult tis-8

sues, where a predominance of angiostatic signals renders9

vascular endothelial cells (ECs) quiescent (Distler et al.,0

2003). One of the few exceptions is the female repro-

ductive tract, in which a fine balance between pro- and2

antiangiogenic signals determines EC activation as part3

of a physiological response during the reproductive cycle4

and pregnancy. The pivotal importance of this process for5

reproduction is demonstrated by the finding that a sin-6

gle dose of anti-angiogenic compounds (i.e., AGM-1470)7

applied either before or during implantation disrupts8

decidualization and placental development in mice, result- 319

ing in embryo resorption (Klauber et al., 1997). Decidual 320

angiogenesis however, differs from stromal decidualiza- 321

tion in depending on the presence of the embryo (Ma et al., 322

1997), which highlights the importance of a coordinated 323

action of signals derived both from the maternal and fetal 324

compartments in the control of vascular expansion during 325

early pregnancy. 326

3.1. Uterine NK cells support vascular remodeling and 327

angiogenesis during early pregnancy 328

Angiogenesis involves the expansion of pre-existing 329

vessels through proliferation of ECs and their subsequent 330

migration and differentiation to form new capillary tubes 331

(Distler et al., 2003). A prior requirement to EC proliferation 332

is an increased vascular permeability and their detachment 333

from smooth muscle cells and extracellular matrix com- 334

ponents. While not representing angiogenesis per se, the 335

initial stages of spiralartery remodelingas observed during 336

mouse and human early pregnancy also involve the abla- 337

tion of the endothelium and smooth muscle of the arterial 338

walls as well as the reorganization of extracellular matrix 339

components. This process appears to be mainly mediated 340

by uNK cellderivedIFN, asthiscytokine has been found to 341

amelioratethe decidual phenotype observed in the absence 342

of uNK cells (Ashkar et al., 2000). Besides impeding an ade- 343

quate blood flow to the implantation site the undilated 344

vessels observed in uNK cell deficient mice would also 345

render EC unable to normally respond to pro-angiogenic 346

signals within the decidualizing microenvironment. In this 347

context, the functions ascribed to NK cells in the remodel- 348

ing of spiral arteries could also be pivotal in the onset of 349

angiogenic responses in the decidua. 350

In several mammalian species, mature uNK cells rep- 351

resent themselves a source of several cytokines and 352

vasoactive mediators which may direct angiogenesis dur- 353

ing implantation and placental development (Leonard 354

et al., 2006; Li et al., 2001). For instance, in vitro and 355

in vivo studies have shown that both human and mouse 356

uNK cells respond to IL-15 by up-regulating the expres- 357

sion of vascular endothelial growth factor (VEGF) isoforms 358

and placenta growth factor (PLGF), two related proteins 359

with potent pro-angiogenic effects (Leonard et al., 2006; 360

Hanna et al., 2003). Interestingly, VEGF-C secretion by 361

human uNK cells has been associated with a self-directed 362

mechanism controlling the cytotoxic activity of these cells 363

(Kalkunte et al., 2009), providing a link between their 364

pro-angiogenic and immunoregulatory functions within 365

the uterine microenvironment. While similar mechanisms 366

have yet to be explored during mouse pregnancy, it is con- 367

ceivable that the high mobility conferred to uNK cells by 368

the unique repertoire of receptors allowing them to recog- 369

nize and respond to trophoblast-derived signals may not 370

only be important for their role as components of innate 371

immunity, but would also give them the ability to guide 372

maternal angiogenesis through VEGF production (Hanna 373

et al., 2003). It is nevertheless worthmentioning thatrather 374

than antigen recognition, the regulation of uNK cell VEGF 375

expression and their interaction with ECs appears to be 376

more dependent on the local cytokine milieu and oxygen 377







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Fig. 2. Depletion of pDC neither affected pregnancy outcome nor the number of implantation in mice. (A) Frequency of fetal loss of Balb/c mated C 57BL/6

females at day 13.5 of pregnancy, that were treated with anti-MIPC clone 120G8 antibody (single injection of 150 × g i.p.) on gestation day 3.5, 7.5 and

11.5 or control antibody (C). Percentage is shown as mean standard error of mean (SEM). (B) Total number of implantations per C57BL/6 female mouse

(mean± SEM).

tension within the human decidualizing microenviron-

ment (Kalkunte et al., 2008).

3.2. DC derived signals directly promote angiogenesis in

the decidua

First identified in pathological settings (i.e., tumor

growth and experimental endometriosis) (Curiel et al.,

2004; Fainaru et al., 2008), the production of vasoactive

mediators by DC may also be important for the control of

the normal angiogenic responses that characterize embryo

implantation. Both in mice and humans this notion is high-

lighted by the preferential location of uDC during early

pregnancy, where they are often associated with the decid-

ual vasculature and show the ability to produce VEGF

(Barrientos et al., 2009) and its receptors VEGFR1 and

VEGFR2 (Plaks et al., 2008; Scholz et al., 2008).

The CD11c-DTR transgenic mouse model has provided

strong evidence on the pro-angiogenic functions of DC dur-

ing early pregnancy. The normal expansion of the decidual

vascular zone fails to occur in the absence of DC, as evi-

denced by the decreased expression of the EC markers

PECAM-1 and endoglin observed in DC depleted implan-

tation sites (Krey et al., 2008). Additionally, DC depletion

during implantation interfered with the normal dynam-

ics of vascular remodeling by affecting vessel permeability

and blood flow to the implantation site (Plaks et al., 2008).

However, as a common feature of DC depleted implanta-

tion sites is the reduced accumulation of mature uNK cells

(Karsten et al., 2009; Krey et al., 2008), further studies are

required to dissect the specific contributions of each cell

subsetto thevascular phenotypeassociated with DC deple-

tion.

Screening of DC depleted implantation sites by differ-

ent experimental approaches gave the first insights into

the mechanisms mediating the pro-angiogenic functions

of decidual DC. For instance, the finding that uDC pro-

duce the soluble isoform of VEGFR1 and TGF-1 (Plaks

et al., 2008) together with the decreased expression of

the TGF-1 receptor endoglin on decidual ECs (Krey et al.,

2008) demonstrate the influence of DC on classical pro-

angiogenic pathways during implantation. The expression

of phosphatydilinositol transfer protein beta (PITP-), a 418

cytosolic protein involved in phospholipid trafficking to 419

cell membranes, is also decreased upon DC depletion (Krey 420

et al., 2008) and might represent an indirect mechanism 421

modulating VEGF expression by affecting the PI3K/Akt sig- 422

naling pathway in endometrial cells (Yoshie et al., 2009). 423

The absence of DC also leads to impaired differentiation 424

of trophoblast giant cells, which are known to produce 425

several vasoactive mediators regulating placental angio- 426

genesis (Cross et al., 2002). Thus, we have demonstrated 427

that DC depletion significantly decreases giant cell expres- 428

sion of proliferin (Krey et al., 2008), a placental hormone 429

that promotes EC migration and vascularization (Cross 430

et al., 2002). 431

4. Concluding remarks 432

The evidence presented suggests that uNK cell recruit- 433

ment is one of the many endometrial adaptations 434

induced during normal decidualization to promote vascu- 435

lar changes that assist the growth and differentiation of 436

stromal cells, which gains more importance during pla- 437

cental development as gestation advances. In contrast, DC 438

appear to act in an upstream position within the uterine 439

milieu, determining the outcome of implantation through 440

their direct influence on crucial processes such as stromal 441

cell proliferation and decidual angiogenesis as well as their 442

ability to modulate uNK cell functions. Furthermore, the 443

identification of novel DC associated pro-angiogenic sig- 444

nals may have important implications for the treatment 445

of pregnancy disorders arising from defective angiogenesis 446

and vascular remodeling during early pregnancy. By allow- 447

ing the morphological and molecular characterization of 448

the decidualizing endometrium in vivo in the absence 449

of signals derived from these cell subsets, mouse mod- 450

els have greatly improved our understanding of DC and 451

NK cell functions during early pregnancy. However, the 452

proven influence of DC derived signals in the promotion of 453

uNK cell recruitment and differentiation still precludes us 454

from identifying specific functions played by each subset 455

individually on the regulation of stromal cell differenti- 456

ation and vascular development and remodeling during 457







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the decidualization process. In this regard, experimental8

approaches combining genetic engineering technologies9

and pharmacological methods allowing the simultaneous0

depletion of DC and NK cells in vivo from the pregnant

uterus would provide further insights on individual and2

cooperative effects mediated by these cells on endome-3

trial stromal cells and the vascular endothelium, greatly4

improving our understanding of the regulatory pathways5

involved in endometrial decidualization.6

Uncited referenceQ17

Sharkey and Smith (2003).8

Acknowledgements9

We apologize to the many authors whose excellent0

papers could not be cited in this review for space limita-

tions. G.B. received a doctoral scholarship from the Charité2

Stiftung. The work discussed in this review was supported3

by Habilitation training grant from the Charité, Sonnenfeld4

Stiftung, Deutsche Forschungsgemeinschaft (BL 1115/1-1)5

and Fritz Thyssen Stiftung (Az. 10.10.2.125) to S.M.B.6

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