The human placenta is a haemomonochorial dually perfused organ which allows transfer of oxygen and nutrients from maternal blood to fetal blood. It is composed of chorionic villous trees containing fetal capillaries, which float in inter-connected maternal blood lacunae. These capillaries pick up oxygen and nutrients, and transport replenished blood back to the fetus via conduit vessels, the chorionic plate venous network and single umbilical vein. The haemodynamics here and the fetal vascular integrity influence solute uptake and oxygenation.
Maternal blood emerges from decidual spiral arteries and empty into the numerous maternal lacunae (intervillous space, IVS) of placental cotyledons. The blood returns back to the maternal circulation via decidual veins in the septa of lobules and cotyledons and marginal sinus exits. The haemodynamics of this circulation is also critical for fetal development, yet the patterns of maternal flow within the intervillous space (IVS) and details of venous return remain largely unknown. Furthermore, there is poor consensus on oxygen gradients within the intervillous space (IVS) and how the partial pressure of gas differs between normal and high-risk pregnancies.
We have used the dually perfused ex vivo term placenta, complementary fetal endothelial cell culture and magnetic resonance imaging (MRI) of the human placenta in utero and ex vivo, to obtain new insights into the function of the human placenta. MRI revealed slow net flow and high net oxygenation in the placenta consistent with efficient delivery of oxygen from mother to fetus. The experimental evidence comparing normal and complicated pregnancies substantiated previous hypotheses on the effects of spiral artery remodelling in utero and also indicated rapid venous drainage from the placenta. We identified a new physiological phenomenon, the ‘utero-placental pump’, by which the placenta contract independently of the rest of the uterus, expelling de-oxygenated maternal blood from the intervillous space. Tracer (Evans blue) introduced to the maternal circuit of ex vivo perfused placental cotyledons confirmed the role of septal veins and marginal sinus exits for de-oxygenated blood and differences therein in placentae from high risk pregnancies. The peak efficiency of oxygen uptake by the placentone was measured in ex vivo perfusions and indicated significant differences in low and high risk groups.
Hydrophilic solutes have to cross the syncytiotrophoblast and the endothelium to reach the fetal blood. The endothelial layer acts as a barrier in series by containing well-defined junctions (adherens and tight junctions). Disruption here leads to reduced junctional restrictiveness, , increased solute transit time and paracellular vascular leaks, all impacting on optimal nutrient delivery. Perfusion studies revealed a significant increase in the percentage of vessels showing extravasation of exogenous 76Mr dextran in pregnancies complicated by gestational (GDM) and Type 1 diabetes. Loss of tight junctional Occludin isoform-A linked to an increased expression of microRNA miR-181a-5p, were a pre-dominant feature of diet-controlled GDM. Treatment with metformin appeared to normalise these effects. VE-cadherin dynamics were also intimately linked to altered ratio of VEGF-A 165a/b in diabetic pregnancies and could be induced experimentally by perfusion of the normal placentae with VEGF-A 165a, with restoration by VEGF165b. The exquisite cross talk between the two circulations allow correct oxygen and solute transfer to ensure fetal well-being and minimise risks of still birth. Ethics: participants were recruited (and placentae obtained) from Nottingham University Hospital Trust with full ethical permission and after informed consent.