Oxygen as modulator of trophoblast invasion

Abstract

At the time of blastocyst implantation the uterine spiral arteries have already undergone morphological changes in the absence of any extravillous trophoblast invasion. Only 2 weeks after implantation, extravillous trophoblast cells develop and come into first contact with decidual tissues. Invading through the decidual interstitium, extravillous trophoblasts potentially reach and transform spiral arteries into uteroplacental arteries. Spiral arterial erosion starts at about mid-first trimester, whereas flow of maternal blood into the intervillous space is continuously established only at the beginning of the second trimester. One key regulator of the number of extravillous trophoblasts is oxygen. The steep gradient in oxygen concentration within the first trimester placenta is diminished with the onset of maternal blood flow. This gradient is used by the trophoblast to generate a large number of invasive cells to adapt the arterial vasculature in the placental bed to the growing needs of the fetus. Changes in oxygen concentrations or other factors leading to alterations in the rates of proliferation and/or apoptosis of extravillous trophoblast clearly impact on the remodelling of the vessels. The respective consequences of a failure in trophoblast invasion are growth restrictions of the baby and perhaps other pregnancy complications.

Fig. 1

Double tissue confrontation assay using placental tissues at a gestational age of 6 weeks. Cryosections were stained with the monoclonal antibody MEM-G9 to visualize HLA-G, a specific marker for extravillous trophoblast. (A,B) Placental villous explants (v) firmly attach to the re-epithelialized decidual tissue (d). Outgrowing extravillous trophoblasts do not invade decidual tissues but rather only migrate on top of the decidual epithelium (blue arrows in B). (C,D) Placental villous explants (v) firmly attach to the non-epithelialized decidual tissue (d). Outgrowing extravillous trophoblasts deeply invade into the decidual tissues (green arrows in D). Magnification (A,C) 50×, (B,D) 100×.

Fig. 2

Schematic representation of placenta and embryo at about weeks 8–10 of gestation. The embryo rests in its amnionic cavity and is connected to the placenta via the developing umbilical cord. The placenta shows a clear developmental gradient (arrow on the left) with the highest level of development at the site of implantation, i.e. at the embryonic pole. This developmental gradient can be found as well in the extent of extravillous trophoblast plugging of spiral arteries (arrow on the right). The bar in the centre represents the oxygen gradient from the placental bed (pO₂ 70 mm Hg) to placenta (pO₂ < 20 mm Hg) and embryo (pO₂ << 20 mm Hg). The dotted line indicates where plugging of spiral arteries generates the oxygen gradient towards the embryo. For further details on the changes at the end of the first trimester see also Figure 2 in Jauniaux et al. (2006) and Figure 4 in Burton (in press).