THE PATHOLOGY OF TROPHOBLASTIC INVASION

 

The main branch of each uterine artery enters the uterus just above the cervix and ascends along the lateral part of its wall. These peripheral branches give rise to arcuate arteries that derive their name from the arching pattern in the uterus. The arcuate arteries give off multiple branches of penetrating vessels called radial arteries. As the radial arteries approach the uterine cavity they become spiral arteries

THE NON PREGNANT STATE

 

In the non-pregnant state the uterine vessels carry less than 1% of the maternal cardiac output (1). This is not surprising in light of the fact that a nonpregnant women only needs to maintain a uterus that weighs 50 g. At term these same vessels must support a uterus, placenta and fetus that can weigh up to 5,000 g.

Poiseuille’s law of fluid flow in a cylinder reveals that flow is proportional to the radius to the fourth power (2). Comparison of vessels in the nonpregnant uterus to those at term reveals that these vessels can increase their radii by as much as ten fold. This translates into an increase in blood flow by a factor of 10,000. Clearly the ability of uterine vessels to vary in diameter is a great advantage.

 

 

INVASIVE TROPHOBLASTS, DECIDUALIZATION AND MENSTRUATION

 

Invasive trophoblasts are the key to the modulation of the state of the uterine vessels (3). These unique cells leave the placenta, penetrate the endometrium and upper layers of the myometrium, selectively permeate the uterine spiral arteries and modify these vessels to yield widened, low resistance vascular channels that carry the markedly increased maternal blood flow to the placenta. This represents a very delicate balancing of conflicting biological needs between the mother and fetus. The fetus, on the one hand, requires its invasive trophoblasts to aggressively penetrate the mother’s uterus in search of vessels to modify. The mother, on the other hand, must protect herself from the invasive trophoblasts, lest they completely penetrate her uterus, causing her to hemorrhage and bleed to death.

FORMATION OF INVASIVE TROPHOBLASTS

 

Two types of trophoblasts have been traditionally described: the cytotrophoblast and the syncytiotrophoblast. The cytotrophoblast; the endocrinologically active villous syncytiotrophoblast; the junctional trophoblast that attaches the anchoring villi to the maternal decidua at Nitabuch’s layer; and the invasive intermediate trophoblast that migrates into the decidua, the myometrium and finally the spiral arteries of the uterus (4).

Cytotrophoblast:

-                 The stem cell of the placenta.

                    -          Gives rise to the differentiated forms of trophoblasts.

-                    Within the chorionic villi, cytotrophoblasts fuse to form the overlying syncytiotrophoblast.

-                    The villous syncytiotrophoblast makes the majority of the placental hormones, the most studied being hCG.

-                    At the point where chorionic villi make contact with external extracellular matrix, a population of trophoblasts proliferates from the cytotrophoblast layer to form the second type of trophoblast—the junctional trophoblast. The junctional trophoblasts make a unique fibronectin—trophouteronectin (TUN)—that appears to mediate the attachment of the placenta to the uterus. TGFß, and more recently, leukemia inhibitory factor (LIF), have been shown to down regulate hCG synthesis and upregulate TUN secretion.

-                    A third type of trophoblast differentiates towards an invasive phenotype and leaves the placenta entirely. The invasive intermediate trophoblast, in addition to making human placental lactogen, also make urokinase-type plasminogen activator (u-PA) and type 1 plasminogen activator inhibitor (PAI-1)..

 

Decidualization

In order to protect the mother from the onslaught of invasive trophoblasts migrating towards the uterine spiral arteries, the endometrial stroma transforms itself into a dense cellular matrix known as the decidua (5). The decidua impedes the movement of invasive trophoblasts both by forming a physical barrier to cell penetration and by generating a local cytokine milieu that promotes trophoblast attachment rather than invasion.(6-10). The fate of the invasive trophoblasts is, in part, likely the result of the balancing of the invasive promoting proteases made by the trophoblasts and the inhibitors of invasion made by the decidua(11-14).

The first signs of the decidualization reaction can be seen as early as day 23 (10 days after the peak of the LH surge) of the normal menstrual cycle when the spiral arteries of the endometrium first become prominent (15). Over the next few days the stromal cells surrounding the spiral arteries become increasingly eosinophilic and enlarged as the differentiating effects of progesterone transforms these cells into predecidual cells (16). The progressive decidualization of the endometrial stroma in the later part of the menstrual cycle prepares the uterine lining for the presence of the invasive trophoblasts, but simultaneously closes the door to implantation(17,18). While the state of the endometrium in the later part of the cycle is ideal to protect the mother from the invasive trophoblasts in the event of a pregnancy, it is entirely unsuited for implantation. 

Menstruation

Menstruation, the breakdown and sloughing of the endometrial lining at the end of a hormonally driven cycle, and is a mechanism by which the endometrium reestablishes a receptive phase following a cycle of nonconception. 

   

Trophoblast Invasion

The morphologic aspects of human trophoblast invasion has been examined in great detail over the last twenty years (12, 19-28).

Examination of monkey implantation sites has revealed that trophoblasts begin to migrate down into the maternal spiral arteries as early as 10 days after fertilization, and at 14 days, many of the spiral arteries beneath the conceptus are totally occluded (29). The specificity of this vascular interaction is revealed by the fact that no such invasion takes place in the veins.

 

Hustin and Schaaps, using anatomic and ultrasonographic approaches, suggested that there is in fact trophoblast plugging of the maternal spiral arteries and a coincident decrease in maternal perfusion of intervillous space up until 12 weeks of gestation (30).

Rodeshch et al. (31). then hypothesized that it is critical that maternal blood flow to the embryo be limited very early in gestation to protect the conceptus from excessively high oxygen levels during critical, early stages of differentiation.

This concept was supported by Coppens et al. (32) serial ultrasounds on normal pregnant women between 8 and 14 weeks showed no uteroplacental blood flow in the first trimester but a significant increase at approximately 12 weeks, which reached maximal levels at 14 weeks.

Burton et al. critically examined the Boyd Collection, 12 early-pregnancy hysterectomy specimens ranging from 43 to 130 days of gestation housed in the Department of Anatomy at the University of Cambridge, and showed that there was significant blockage of the maternal spiral arterioles by trophoblasts at points of contact with the intervillous space between 6 and 8 weeks but that this blockage was gradually eliminated between 8 and 12 weeks of gestation (33).

If we accept trophoblast plugging and the first trimester low-flow concept, one question remains: how are the first trimester embryo’s nutritional needs met? Hustin and Schaaps suggested that the intervillous space is bathed by an acellular fluid that could be plasma filtered by the trophoblastic shell.

 Burton and colleagues have offered another possibility. By examining multiple human implantation sites preserved in the Boyd collection (33), these investigators noted that below openings to the intervillous spaces there were dilated endometrial glands. It is well known that the endometrial glands of early pregnancy are characterized by hypersecretion (34). 

Burton and colleagues have suggested that secretions from the hypersecretory endometrial glands contribute nutrients to the embryo in the first trimester. Concomitant with endovascular plugging of the maternal spiral arteries, the process—of trophoblast penetration of the maternal spiral arteries and their conversion to low-resistance channels—begins

The first trimester low-flow concept has not been universally accepted (35-37).

Jauniaux et al. (38) report the direct documentation of a significant increase in placental intervillous oxygen tension, and hence maternal perfusion of the placenta, between 8 and 12 weeks of gestation. This group has also reported in this article that coincident with this increased perfusion and oxygen tension within the placenta between 8 and 12 weeks there is a corresponding increase in anti-oxidant systems, including catalase, glutathione peroxidase and superoxide dismutase, presumably to counteract the oxidative stress of the increased intervillous perfusion and oxygen tension. 

 

UTEROPLACENTAL BLOOD FLOW IN PEGNANCY

 

The action of the invasive trophoblasts on the maternal spiral arteries leads to a very low resistance uteroplacental circulation which facilitates the marked increase in blood flow seen in these vessels at term. Utilizing a variety of techniques, many groups have estimated the amount of blood flow into the gravid uterus (39-43). This work has demonstrated that at term a women’s total blood volume increases by about 40% compared to her nonpregnant state (44). Concomitantly, her cardiac output rises 30-35% and the total uteroplacental blood flow increases to about 25% of her total cardiac output (45,46). Direct measurements of uterine blood flow in the nonpregnant state have shown a combined uterine artery flow in the follicular phase to be approximately 45 mL/min (47), while the total uterine flow at term has been estimated to be as high as 750 mL/min (40), representing an almost 17-fold increase in flow to the uterus. Improvements in techniques to estimate blood flow in the gravid uterus have suggested that this last calculation may be too high. Thaler et al.(43) used a transvaginal duplex Doppler ultrasonography system to compare the blood flow characteristics in the ascending uterine artery before and during pregnancy in the same patient and determined that there was a 3.5-fold increase in blood flow—still a significant increase in total blood flow to the gravid uterus.

 

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