Interactions between Trophoblast Cells and the Maternal and Fetal Circulation in the Mouse Placenta

Abstract

Mammalian embryos have an intimate relationship with their mothers, particularly with the placental vasculature from which embryos obtain nutrients essential for growth. It is an interesting vascular bed because maternal vessel number and diameter change dramatically during gestation and, in rodents and primates, the terminal blood space becomes lined by placental trophoblast cells rather than endothelial cells. Molecular genetic studies in mice aimed at identifying potential regulators of these processes have been hampered by lack of understanding of the anatomy of the vascular spaces in the placenta and the general nature of maternal-fetal vascular interactions. To address this problem, we examined the anatomy of the mouse placenta by preparing plastic vascular casts and serial histological sections of implantation sites from embryonic day (E) 10.5 to term. We found that each radial artery carrying maternal blood into the uterus branched into 5-10 dilated spiral arteries located within the metrial triangle, populated by uterine natural killer (uNK) cells, and the decidua basalis. The endothelial-lined spiral arteries converged together at the trophoblast giant cell layer and emptied into a few straight, trophoblast-lined "canals" that carried maternal blood to the base of the placenta. Maternal blood then percolated back through the intervillous space of the labyrinth toward the maternal side of the placenta in a direction that is countercurrent to the direction of the fetal capillary blood flow. Trophoblast cells were found invading the uterus in two patterns. Large cells that expressed the trophoblast giant cell-specific gene Plf (encoding Proliferin) invaded during the early postimplantation period in a pattern tightly associated with spiral arteries. These peri/endovascular trophoblast were detected only approximately 150-300 microm upstream of the main giant cell layer. A second type of widespread interstitial invasion in the decidua basalis by glycogen trophoblast cells was detected after E12.5. These cells did not express Plf, but rather expressed the spongiotrophoblast-specific gene Tpbp. Dilation of the spiral arteries was obvious between E10.5 and E14.5 and was associated with a lack of elastic lamina and smooth muscle cells. These features were apparent even in the metrial triangle, a site far away from the invading trophoblast cells. By contrast, the transition from endothelium-lined artery to trophoblast-lined (hemochorial) blood space was associated with trophoblast giant cells. Moreover, the shaping of the maternal blood spaces within the labyrinth was dependent on chorioallantoic morphogenesis and therefore disrupted in Gcm1 mutants. These studies provide important insights into how the fetoplacental unit interacts with the maternal intrauterine vascular system during pregnancy in mice.

Localization and subcellular distribution of prolyl oligopeptidase in the mouse placenta

“…For example, POP might degrade some peptides that are present only around these stages. It might also be related to differentiation of some placental cells including the syncytiotrophoblast (Rossant and Cross, 2001) or play some role in the establishment of fetal-maternal connection (Adamson et al, 2002). In contrast, POP in the spongiotrophoblast and TGCs might be involved in the secretion of hormones and growth factors because POP was suggested to control protein secretion in human glioma cells (Schulz et al, 2005).…”

Paternal MHC expression on mouse trophoblast affects uterine vascularization and fetal growth

“…Previous studies on E13.5 placentas suggested that uNK cells are separated from the farthest distal trophoblast cells by a considerable distance (5). Because the remodeling of uterine arteries is initiated much earlier during the phase of trophoblast giant cell invasion, we analyzed midsagittal sections of E8.5 conceptuses for the relative distribution of uNK and trophoblast cells, detected by staining with Dolichus biflores agglutinin (DBA) and pancytokeratin, respectively (5,33). At this stage it was obvious that trophoblast cells in the mesometrial decidua were surrounded by large numbers of uNK cells, some of which had infiltrated the ectoplacental cone (Fig.…”

“…This situation is particularly evident in hemochorial placentation (found in humans and mice), where fetal trophoblast cells penetrate deeply into the maternal decidua and come into direct contact with maternal blood and tissues (3). During this invasive process, trophoblast cells transform the uterine arteries into large canals that funnel maternal blood toward the implantation site (4)(5)(6). Spiral artery remodeling is initiated early after implantation and is critical for the establishment of a fully functional placental nutrient and gas exchange unit throughout further development.…”

“…uNK cells differ from peripheral NK cells in that they have a reduced lytic activity and a distinct surface receptor repertoire (14)(15)(16)(17). uNK cells support neovascularization of the decidua by producing proangiogenic and endothelial mitogenic stimulants and contribute to arterial transformation by initiating the loss of the arterial media (5,14,18,19). In uNK cell-deficient mice the arteries do not undergo the dilation that is normally observed during pregnancy, and the resulting decrease in maternal blood supply may be associated with small placental size and embryonic lethality (20,21).…”

“…Surface expression of MHC antigens and their functional effect on uNK cells raised the question of whether trophoblast cells physically interact with uNK cells to influence their activity. Previous studies on E13.5 placentas suggested that uNK cells are separated from the farthest distal trophoblast cells by a considerable distance (5). Because the remodeling of uterine arteries is initiated much earlier during the phase of trophoblast giant cell invasion, we analyzed midsagittal sections of E8.5 conceptuses for the relative distribution of uNK and trophoblast cells, detected by staining with Dolichus biflores agglutinin (DBA) and pancytokeratin, respectively (5,33).…”