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Endovascular Trophoblast Invasion: Implications for the Pathogenesis of Intrauterine Growth Retardation and Preeclampsia

Department of Anatomy II, University of Technology Aachen, D-52057 Aachen, Germany

	ABSTRACT

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Maternal uteroplacental blood flow increases during pregnancy. Altered uteroplacental blood flow is a core predictor of abnormal pregnancy. Normally, the uteroplacental arteries are invaded by endovascular trophoblast and remodeled into dilated, inelastic tubes without maternal vasomotor control. Disturbed remodeling is associated with maintenance of high uteroplacental vascular resistance and intrauterine growth restriction (IUGR) and preeclampsia. Herein, we review routes, mechanisms, and control of endovascular trophoblast invasion. The reviewed data suggest that endovascular trophoblast invasion involves a side route of interstitial invasion. Failure of vascular invasion is preceded by impaired interstitial trophoblast invasion. Extravillous trophoblast synthesis of nitric oxide is discussed in relation to arterial dilation that paves the way for endovascular trophoblast. Moreover, molecular mimicry of invading trophoblast-expressing endothelial adhesion molecules is discussed in relation to replacement of endothelium by trophoblast. Also, maternal uterine endothelial cells actively prepare endovascular invasion by expression of selectins that enable trophoblast to adhere to maternal endothelium. Finally, the mother can prevent endovascular invasion by activated macrophage-induced apoptosis of trophoblast. These data are partially controversial because of methodological restrictions associated with limitations of human tissue investigations and animal studies. Animal models require special care when extrapolating data to the human due to extreme species variations regarding trophoblast invasion. Basal plates of delivered placentas or curettage specimens have been used to describe failure of trophoblast invasion associated with IUGR and preeclampsia; however, they are unsuitable for these kinds of studies, since they do not include the area of pathogenic events, i.e., the placental bed.

apoptosis, early development, placenta, syncytiotrophoblast, trophoblast

	INTRODUCTION

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During the first half of human pregnancy, uteroplacental arteries undergo a series of pregnancy-specific changes that include 1) apparent replacement of endothelium and media smooth muscle cells by invasive trophoblast, 2) loss of elasticity, 3) dilation to wide, incontractile tubes, and 4) loss of vasomotor control [1] (Fig. 1A and B). There is general agreement that spiral artery remodeling reduces maternal blood flow resistance and increases uteroplacental perfusion to meet the requirements of the fetus. Moreover, the loss of contractility and maternal vasomotor control guarantees maternal blood supply to the placenta, irrespective of maternal attempts to regulate the blood distribution within the body [2, 3].

View larger version (39K): [in this window] [in a new window]   FIG. 1. Schematic representation of interstitial and endovascular trophoblast invasion in human pregnancy before Week 6 of gestation (A), after Week 20 of normal gestation (B), and after Week 20 of gestation in preeclampsia and/or IUGR (C). Blue: fetal tissues. Red: maternal tissues. ps: zone of placental separation, where the basal plate (above, attached to the placenta) separates from the placental bed (remaining in the uterus after delivery). Note that failure of endovascular trophoblast invasion in IUGR and preeclampsia (C) is restricted to the placental bed and does not affect segments of the uteroplacental arteries in the later basal plate of the placenta

In 1972, Brosens and coworkers [4] described reduced trophoblast invasion and absence of pregnancy-specific changes of uteroplacental arteries in placental bed specimens from pregnancies associated with intrauterine growth retardation (IUGR) often combined with preeclampsia (Fig. 1C) [4, 5]. Since that time, endovascular trophoblast invasion has been one of the major foci of placental research. The accepted core hypothesis is that reduced endovascular trophoblast invasion and uteroplacental artery remodeling are key pathologic features of IUGR and preeclampsia. However, hypotheses about the molecular mechanisms that regulate trophoblast invasion and uteroplacental artery remodeling are still controversial. The aims of this review are to reevaluate these controversial hypotheses that explain the regulation of endovascular trophoblast invasion and uteroplacental artery remodeling, evaluate the various supporting data, and provide a basis for new research aimed at understanding the leading cause of maternal death: preeclampsia.

	DEFINITION OF TERMS

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During implantation and subsequent trophoblast invasion, fetal trophoblast cells and maternal uterine tissues (endometrium and myometrium) come into intimate contact with each other. The resulting zone of mixed origin is called the maternofetal junctional zone (Fig. 1B). Those parts that adhere to the placenta after delivery and form the bottom of the intervillous space are called the basal plate (Fig. 1B). The remaining parts of the junctional zone that adhere to the uterine wall after delivery make up the placental bed (Fig. 1B).

All trophoblast cells residing outside the placental villi are summarized under the term extravillous trophoblast (Fig. 1A). In the basal plate, the extravillous trophoblast forms proliferating clusters of stem cells, so-called cell columns. The latter connect so-called anchoring villi to the basal plate (Fig. 1A). The nonproliferative, invasive daughter cells of the cell columns that invade the uterine interstitium comprise the interstitial trophoblast (Fig. 1A). Those invasive extravillous trophoblast cells that infiltrate arterial walls and lumens make up the endovascular trophoblast (Fig. 1B). Both the route of trophoblast invasion from the proliferating stem cells of the cell columns into the placental bed and the route from cell columns into the uteroplacental arteries are summarized as the invasive pathway (Fig. 2B).

View larger version (44K): [in this window] [in a new window]   FIG. 2. Hypothetical routes of endovascular trophoblast invasion. Blue: fetal tissues, including interstitial trophoblast and its intravasating derivatives. Green: extravasation route of endovascular trophoblast. Red: maternal tissues. Note that in the hypothetical case of extravasation (A), the endovascular trophoblast cells invade via the arterial lumen and are derived from an unknown origin. In the rhesus monkey, this source is said to be the trophoblastic shell, which, however, in the human vanishes before trophoblast invasion. By contrast, in the more likely case of intravasation (B), endovascular trophoblast is derived from cell columns via the interstitial invasion route

	PHYSIOLOGICAL CHANGES OF SPIRAL ARTERIES

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Remodeling of maternal uterine spiral arteries is crucial for normal growth and development of the fetus. Remodeling of uteroplacental arteries, the so-called physiological changes of uteroplacental arteries, can be divided according to structural criteria into three stages: 1) trophoblast invasion-independent vascular changes, 2) vascular remodeling induced by perivascularly located interstitial trophoblast, and 3) trophoblast infiltration of vessel walls. IUGR follows trophoblast malinvasion of the uteroplacental arteries. In these pregnancies, the failure of arterial remodeling results in malperfusion of the placenta. The role of each of the three stages in failure of uteroplacental artery remodeling remains open. It is very likely that only the full sequence of events guarantees a degree of arterial dilation adequate to sufficiently perfuse the placenta throughout all stages of pregnancy.

Trophoblast Invasion-Independent Vascular Changes

The initial changes to uteroplacental arteries involve a generalized perturbation of these arteries, endothelial basophilia and vacuolation, disorganized vascular smooth muscle, and lumen dilation [6]. The pregnancy-induced changes in uteroplacental arteries are independent of direct trophoblast invasion and are considered to involve maternal activation of local decidual artery renin-angiotensin systems [6]. Moreover, Craven and coworkers [6] demonstrated that during intrauterine pregnancies spiral arteries from both implantation and nonimplantation regions display these physiological changes. Furthermore, endometrial spiral arteries undergo the same physiological vascular modifications in ectopic pregnancies.

Vascular Remodeling Induced by Perivascularly Located Interstitial Trophoblast

Following trophoblast invasion-independent changes, the uteroplacental arteries within the implantation region are invaded by extravillous trophoblast cells. In a first step, extravillous trophoblast cells in juxtaposition against uteroplacental artery structures are associated with further vascular remodeling. The latter findings, described in the guinea pig [2, 7, 8], comprise reduction of media smooth muscle cells and deposition of fibrinoid material before infiltration of the media by trophoblast. Respective observations in the human have not yet been reported.

Trophoblast Infiltration of Vessel Walls

The third stage of uteroplacental vascular remodeling is characterized by infiltration of the arterial wall by endovascular trophoblast. The uteroplacental arteries undergo further dilation up to several times the original diameter of the lumen [1, 3, 9]. Trophoblast infiltration of the media smooth muscle coincides with loss of elastic fibers [10, 11]. A debate exists regarding whether smooth muscle cells undergo cell death and become replaced by endovascular trophoblast [1] or temporary molecular and structural dedifferentiation [8] during trophoblast invasion. The same question was postulated for the replacement of some of the endothelial cells. Large pleomorphic cells that line uteroplacental arteries within the proximal decidual segments express factor VIII-related antigen but not human chorionic gonadotropin, thus suggesting that not all altered cells without an obvious endothelial phenotype are, in fact, trophoblast cells [12].

	SITES AND ROUTES OF ENDOVASCULAR TROPHOBLAST INVASION

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Endovascular trophoblast invasion is not a homogeneous process. The density of extravillous trophoblast and the depth of invasion of uteroplacental arteries are most pronounced in the central region of the placental bed. The density and depth of invasion of extravillous trophoblast and the degree of invasion of spiral arteries diminish toward the placental margin [13]. Central-region placental bed specimens obtained from normal pregnancies reveal endovascular trophoblast that invaded and dilated uteroplacental arteries up to the first third of the myometrium, a depth similar to interstitial trophoblast invasion in this region. The anatomical pathways taken by endovascular trophoblast have been a matter of controversy between the extravasation and intravasation model.

Extravasation

Based on detailed studies on the rhesus monkey, Blankenship and coworkers [14] concluded that endovascular trophoblast derived from an unknown source gained access to the arterial lumens via or close to their point of confluence with the intervillous space. Thereafter, the cells migrate along the arterial lumens retrograde to blood flow by adhering to and replacing endothelium, locally forming intraluminal trophoblastic plugs (Fig. 2A). Finally, a certain number of these cells were thought to leave the lumen and centrifugally invade media and adventitia.

Intravasation

Based on studies in the human, most researchers favor the contrasting concept of intravasation. Structural criteria [15] and immunohistochemical data [16, 17] revealed that endovascular trophoblast represents an end stage of differentiation of interstitial trophoblast derived from the cell columns. As a side step, a subpopulation of extravillous trophoblast cells invades the arterial walls from the surrounding junctional zone and finally enters the arterial lumens (Fig. 2B). Whether or not the intravasated cells then migrate inside the arterial lumens and even locally may extravasate remains open.

A combination of both hypotheses was suggested by Kam et al. [18]. These authors described infiltration and replacement of arterial media and adventitia by interstitial trophoblast, followed by the replacement of endothelium by a separate population of endovascular trophoblast, the derivation of which was not described.

All of these data on intravasation or extravasation were collected on uteroplacental arteries. By contrast, Craven et al. [19] presented convincing evidence that peripheral villi were directed by the uteroplacental blood flow into marginal veins. These villi adhered to the endothelial surfaces and gave rise to cell columns, the cells of which extravasated the venous walls. This villus-to-vein invasion route requires further investigation. To our best knowledge, it has never been described in uteroplacental arteries.

The answer to the question of whether extravasation or intravasation takes place in uteroplacental arteries is crucial for the understanding of the pros and cons of the various hypotheses described herein. It is important to recognize that extravasation was described in the rhesus monkey, a species with a nearly complete trophoblastic shell that separates the intervillous space and maternofetal junctional zone. This trophoblastic shell may be a source for intraluminal trophoblast migration. In contrast, the trophoblastic shell of the very early gestation human placenta becomes rarified to widely spread cell columns not in contact with the terminal structures of the maternal arteries [3].

The ability of the early trophoblastic shell from the first weeks of pregnancy to be the source of endovascular trophoblast extravasating until the end of pregnancy requires endovascular trophoblast to remain in the cell cycle and to represent a self-replicating population in those stages of pregnancy in which the trophoblastic shell is no longer available. In agreement with the extravasation theory, the endovascular trophoblast in the rhesus monkey has been described by King and Blankenship [20] to maintain proliferation based on proliferating cell nuclear antigen (PCNA) immunohistochemical analysis (PCNA antibody PC10). The PCNA displays a long half-life (20 h or more) [21]; therefore, cells may remain immunopositive for days after leaving the cell cycle. Human endovascular trophoblast has not been observed to proliferate according to Ki67 immunohistochemical analysis, ³H-thymidine incorporation studies, or assessment of mitotic figures. Proliferation of human extravillous trophoblast has been observed exclusively in the trophoblast that rests on the basal lamina of cell columns [22].

We conclude from these data that the extravillous trophoblast that emanates from the cell columns provides cells for the interstitial route of trophoblast invasion. Cells from the latter route invade (intravasate) uteroplacental arteries and contribute to the remodeling process by replacing arterial media and endothelium (Fig. 2B).

	DOES MISSING TROPHOBLASTIC EXPRESSION OF A VASCULAR PHENOTYPE CONTRIBUTE TO MALINVASION OF UTEROPLACENTAL ARTERIES?

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The expression of cell adhesion molecules is necessary for trophoblast invasion because these molecules enable the trophoblast to adhere to the extracellular matrix, form colonies, and target cells in the vessel wall. Numerous studies reported that 1) proliferative and early postproliferative cells within the proximal invasive pathway (immunoreactive with proliferation marker Mib 1) express epithelial adhesion molecules and 2) the nonproliferative trophoblast of the distal invasive pathway (immunonegative with Mib 1) acquires an invasive phenotype by switching its repertoire of adhesion molecules to one resembling that of mesenchymal derivatives [22–24]. Some of these studies [25, 26] suggested that trophoblast that approaches the uteroplacental arteries and replaces the endothelium mimicked the adhesion molecule expression patterns found on endothelial cells.

Zhou et al. [25, 26] introduced the hypothesis that impaired invasion of uteroplacental arteries is due to trophoblastic failure to acquire the vascular repertoire of adhesion molecules. In normal pregnancies, these authors reported a generally reduced expression of E-cadherin in extravillous trophoblast, whereas up-regulating expression of VE-(endothelial) cadherin, platelet-endothelial adhesion molecule-1 (PECAM-1), vascular endothelial adhesion molecule 1 (VECAM-1), and 4-integrins. Endovascular trophoblast continues to express these receptors and, like activated endothelial cells, acquires vß3 [25]. The same group reported that extravillous trophoblast in preeclampsia failed to express most of these endothelial markers and hypothesized that expression of vascular phenotyped trophoblast is required for successful endovascular invasion [26].

However, the trophoblast-endothelial mimicry model has not been supported by other investigators. For example, after studying placental bed biopsy specimens, Lyall and coworkers [27] reported PECAM-1 expression was not detected in extravillous trophoblast but observed only in endothelial cells. Moreover, no differences in cell-type patterns of PECAM-1 expression were observed between normal pregnancy, preeclampsia, and IUGR. Also regarding integrins, the patterns found in normal pregnancies were comparable to those in preeclampsia [28]. Finally, the down-regulation of E-cadherin during trophoblast invasion, described by Zhou et al. [25, 26], was not supported in a later study [29].

A contrasting vascular adhesion hypothesis has been presented by other authors [30–32]. King and Loke [30] described a model of endotheliotrophoblastic interaction, where the maternal endothelium at the implantation site undergoes pregnancy-induced changes that allow their replacement by trophoblast. These authors reported that endovascular trophoblast expresses the cell-surface carbohydrate sialyl-Lewis^x, normally located on leukocytes. This carbohydrate is the cognate ligand of E- and P-selectins. Both these lectins are expressed by endothelium during inflammatory reactions. Leukocytes attach to endothelium via interactions between sialyl-Lewis^x and selectins and subsequently migrate through vessel walls. During pregnancy, maternal endothelial E- and P-selectin expression occurs exclusively at the implantation site [31] and may provide a mechanism for maternal and fetal cell interaction to enable trophoblast to home within the uteroplacental vessel lumens. The sialyl-Lewis^x- E-selectin interaction is also involved in adhesion of cancer cell lines to human umbilical vein endothelial cells in vitro [32].

	DOES MISSING TROPHOBLASTIC SECRETION OF NITRIC OXIDE CONTRIBUTE TO MALINVASION OF UTEROPLACENTAL ARTERIES ONLY IN RODENTS?

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Pregnancy-induced dilation of uteroplacental arteries was considered to result from the destruction of musculoelastic structures of vessels by invading trophoblast [1, 33]. This widely accepted hypothesis is contradicted by the observations that arterial dilation in human pregnancy starts at 8 wk of gestation before invasion of vessels by trophoblast [2, 6, 7, 15]. Guinea pig uteroplacental arteries commence dilating when approached by interstitial trophoblast expressing nitric oxide synthase (endothelial nitric oxide synthase—eNOS—and possibly also inducible nitric oxide synthase—iNOS) [8]. Only the already dilated arteries were subsequently invaded by trophoblast. Moreover, in this species the trophoblast invasion of uteroplacental arteries is not associated with removal of media smooth muscle cells, but rather muscle cells dedifferentiate to myoblasts [8]. These myoblasts redifferentiated to an intact media within a few days after delivery [34].

Lyall et al. [35] could not detect endovascular trophoblast expression of eNOS or iNOS in placental bed biopsy specimens from Weeks 8 to 19 of human pregnancy and have questioned whether the guinea pig data on nitric oxide secretion can be transferred to the human. However, Martin and Conrad [36] reported eNOS expression in human interstitial trophoblast using immunohistochemical and in situ hybridization analysis. Moreover, using a human extravillous trophoblast cell line that expresses both the constitutive (eNOS) and the inducible isoforms (iNOS), Cartwright and coworkers [37] have shown that trophoblast cell motility and invasion strongly depend on trophoblast-derived NOS in vitro.

The question of whether pregnancy-induced dilation by trophoblast-derived nitric oxide is specific only for rodents and human trophoblast in vitro or also occurs in the human in vivo has implications for understanding the pathogenesis of preeclampsia. Chwalisz and Garfield and coworkers [38, 39] reported preeclampsia like biological responses, including hypertension, proteinuria, and fetal growth retardation in rats and guinea pigs following long-term inhibition of NOS with L-NAME.

	DO ACTIVATED MATERNAL MACROPHAGES PREVENT PREGNANCY-INDUCED ADAPTATION OF UTEROPLACENTAL ARTERIES BY INHIBITING INVASION VIA INDUCTION OF TROPHOBLAST APOPTOSIS?

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Our discussion on adaptation of uteroplacental arteries to pregnancy conditions focused largely on intrinsic trophoblastic features associated with invasion. The trophoblastic orientation of the respective hypotheses implied trophoblast failure that caused impaired endovascular trophoblast invasion associated with IUGR or preeclampsia. However, well-known maternal risk factors for preeclampsia and IUGR (renal disease, diabetes, obesity, and psychosocial stress) render it unlikely that trophoblastic failure is the sole pathogenic mechanism. A dominant maternal-factor model used to explain preeclampsia is dysfunction of normal trophoblast immune privilege. A promising maternal pathogenic link might be presented by macrophages.

Maternal macrophages are normal constituents of the placental implantation site and can be demonstrated by antibodies to CD14 or CD68 [40, 41]. Greater numbers of macrophages are found in the decidua basalis compared with the decidua parietalis, where trophoblast invasion is limited. The observations of differential macrophage distributions hint at interactions between trophoblast and macrophages [42]. Macrophages produce and respond to a wide range of cytokines and may be involved in decidual paracrine networks that regulate trophoblast invasion [43, 44]. Activated macrophages produce high levels of tumor necrosis factor (TNF) [44]. One of the cognate receptors of TNF, TNF receptor 1 (TNF-R1), is expressed by trophoblast cells [45], and interactions between TNF and TNF-R1 were described to induce trophoblast apoptosis in vitro [46].

Using an immortalized extravillous trophoblast cell line, we have further substantiated and extended these data [47]. The experiments revealed that activated macrophages induce trophoblast apoptosis by the concerted action of two mechanisms: 1) by secretion of TNF that binds to the trophoblastic TNF-R1 and 2) by secretion of indolamine 2,3-dioxygenase (IDO) that catabolizes and depletes local levels of tryptophan (Fig. 3). These data explain the immunohistochemically evident inverse relation between the amount of endovascular trophoblast and macrophages in the wall of uteroplacental arteries [41] (Fig. 3). The fact that macrophages induce trophoblast apoptosis in vitro renders it unlikely that the increased macrophage population in the arterial walls in preeclampsia is simply due to apoptotic attraction of macrophages [47]. However, combining both possible interactions between macrophages and the trophoblast, it could be hypothesized that macrophage-induced trophoblast apoptosis attracts and activates more macrophages, leading to a vicious cycle. In normal pregnancy, the walls of uteroplacental arteries are largely devoid of macrophages and become invaded by the trophoblast. In contrast, preeclampsia is associated with reduced trophoblast invasion of uteroplacental vessels, and accumulation of apoptotic interstitial trophoblast juxtaposing the arteries correlate with maternal macrophages in the arterial media [47]. In addition, murine macrophage function is inhibited by high-dose progesterone. In particular, expression of iNOS and TNF was reduced [48].

View larger version (65K): [in this window] [in a new window]   FIG. 3. Defense of endovascular trophoblast invasion (via intravasation) by activated maternal macrophages of the arterial walls in preeclampsia and/or IUGR. These macrophages force approaching trophoblast cells into apoptosis by secretion of TNF and IDO, the latter causing local tryptophan depletion. Blue: fetal tissues, including trophoblast. Red: maternal tissues. Lilac: activated maternal macrophages. Note that in the case of preeclampsia activated maternal macrophages are accumulated in the proximal parts of the uteroplacental arteries located in the deeper zones of the placental bed but are missing in the superficial layers of the junctional zone (basal plate)

	IUGR AND PREECLAMPSIA: INCOMPETENT INVASION OF EXTRAVILLOUS TROPHOBLAST OR EXAGGERATED MATERNAL DEFENSE AGAINST INVASION?

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It is generally believed that preeclampsia is associated with a generalized impairment of trophoblast invasion, that is, both interstitial and endovascular trophoblast invasion are reduced. Statements such as "preeclampsia is associated with abnormally shallow placentation" [49], "hypoinvasive placental phenotype characteristic of preeclampsia;" [50], and "shallow trophoblast invasion ... predisposing the pregnancy to preeclampsia" [51] suggest impaired/shallow interstitial trophoblastic invasion results in impaired endovascular trophoblast invasion and leads to maladaptation of uteroplacental arteries. Recent quantitative studies on interstitial trophoblast invasion in hysterectomized uteri from patients with preeclampsia have revealed that both invasive depth and numerical density of interstitial extravillous trophoblast are significantly reduced compared with normal [52]. However, in contrast to previous studies on basal plates from delivered placentas ([53] These authors obviously have studied the basal plate, but erroneously have called it "placental bed.") interstitial trophoblast apoptosis within the placental bed was not increased but rather reduced in preeclampsia [52], whereas endovascular apoptosis was increased [41].

These contrasting apoptosis features let us doubt that shallow trophoblast invasion per se is the cause of impaired endovascular invasion. As already discussed, mere intrinsic trophoblastic phenomena (such as missing expression of a vascular phenotype, reduced nitric oxide secretion by the trophoblast, and altered trophoblast behavior caused by deficient oxygenation [49, 51], the latter issue not discussed in this review) are unlikely to be the exclusive causes of malinvasion of uteroplacental arteries with subsequent IUGR and/or preeclampsia. Rather, clinical and basic research data discussed herein suggest that maladaptation and malinvasion of uteroplacental arteries characteristic of IUGR and preeclampsia result from 1) intrinsic factors, namely abnormal biology of the extravillous trophoblast, acting in concert with 2) extrinsic, maternal uterine factors operating around the uteroplacental arteries, such as impaired decidual remodeling [54, 55], macrophage-based defense mechanisms [41, 47], impaired function of uterine NK cells [56], and maternal endothelial failure to express selectins [30, 31]. Furthermore, it is feasible these factors may interact, resulting in a cascade of events.

	TISSUES AND MODELS FOR THE STUDY OF ENDOVASCULAR TROPHOBLAST INVASION

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The phenomenon of endovascular trophoblast invasion is an area of reproductive biology research in which knowledge remains partly superficial and controversial. The main reason for this is the limitations of research tools available to study endovascular trophoblast in combination with missing awareness of these limitations.

Descriptive studies on human material are handicapped by several facts:

• Easily available, delivered placentas [53] do not cover the zone of interest, the placental bed.
  
• Placental bed biopsy specimens [25–27, 35, 41, 47] are available to only a few groups, have been obtained largely at the time of cesarean section, represent only a small segment of the placental bed, and require special expertise to evaluate.
  
• Hysterectomized uteri [6, 15, 52] are rare and often collected under heterogeneous and pathological conditions. Moreover, it is extremely difficult to collect control cases.
  
• In general, all of the listed samples are available in those early stages of human pregnancy in which the pathogenesis of IUGR and preeclampsia have their origin. However, in these stages, adequate separation between pathological and control groups is impossible since the potential outcome of an interrupted pregnancy is untestable. Alternatively, samples from later stages of pregnancy with obvious signs of disease when compared with normal material will only provide data during overt disease and cannot be used to describe causation.
  

In vitro studies with human cells, cell lines, and tissue explants [25, 45–47, 50, 57] provide well-defined experimental models; however, they are usually limited to one or two cellular players (e.g., cytotrophoblast, cytotrophoblast plus endothelial cells, cytotrophoblast plus macrophages) and therefore cannot mimic the complex interplay of trophoblast, mesenchyme, various maternal immune cells, and the diverse cellular components of and within the vessels. Even the use of tissue explants where complex fetal and maternal tissue structures are maintained cannot solve this problem, since not all of the cellular players remain in the respective state of differentiation during in vitro culture.

Animal experiments [2, 7, 8, 14, 20, 34, 38, 39, 48] solve the problems regarding availability of samples, pregnancy stages, and experimental conditions. However, assuming that trophoblast, endothelium, and macrophages in other species are biologically similar, there are doubts that their interplay in pregnancy is really comparable to that in the human. The seemingly basic phenomenon of endovascular trophoblast invasion is highly variable among ruminants (nonexistent), myomorph rodents (trophoblast invasion is blocked by formation of hyperploid giant cells), human (reaching the superficial myometrium), and caviomorph rodents (with trophoblast invasion extending into extrauterine, intraperitoneal arteries). These facts prevent simple extrapolation of data from any other species to the human.

At present, we cannot solve the general methodological problems inherent in the area of endovascular trophoblast biology. However, we should be aware of the limitations of the various tissues and experimental models when approaching the next generation of research emerging from high-throughput genomic and proteomic strategies.

	ACKNOWLEDGMENTS

 
The authors thank Professor Joan Hunt, University of Kansas Medical Center, Kansas City, KS, for initiating this review.

	FOOTNOTES

 
¹ Correspondence: Peter Kaufmann, Department of Anatomy II, University Hospital Aachen, University of Technology Aachen, Wendlingweg 2, D-52057 Aachen, Germany. FAX: 49 241 80 82 472; pkaufmann{at}ukaachen.de

Received: 23 December 2002.

First decision: 22 December 2003.

Accepted: 26 February 2003.

	REFERENCES

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