Understanding the relationship of blood vessel glycocalyx structure and composition with permeability

The human placenta is an essential organ for the fetus; it protects the fetus from harmful maternal pathogens and immune cells whilst delivering oxygen and vital nutrients from the mother to the fetus. It is haemochorial- placental villi lie bathed in maternal blood and can directly take up nutrients (Fig 1a). These solutes have to cross an outer syncytiotrophoblast layer and an underlying fetal endothelium to enter fetal blood (Fig 1b). Both layers provide resistance in series; pathology here lead to compromised fetal growth and later cardiovascular disease (fetal origin of disease). Pilot studies in Leach lab demonstrated that the syncytiotrophoblast has an extensive glycocalyx layer- a potential third layer of resistance (Fig 1c).

Fig 1a- Placental villi, containing fetal blood vessels, lying bathed in maternal blood; Fig 1b -2 Layers separate maternal and fetal blood; Fig 1c- An extensive glycocalyx (green) cover the outer lining of all placental villi. Note some fetal vessels (red) also have luminal glycocalyx.

In other systems, the endothelial surface glycocalyx (GLX) layer has been proven to provide large resistance to solute transport [1]. GLX carry negative charge, which deter charged solutes. GLX has been shown to initiate vasodilation, via the eNOS and nitric oxide pathway and alter blood flow [2]. Thus, the urgent questions this project will ask are: What is the function of this layer in the placenta? Is it hindering solute transport or filtering what may or may not get across? Does it ensure maximal vasodilatation of maternal flow to the placenta for optimal nutrient delivery? To address these questions this project will look at the composition of the placental glycocalyx from normal pregnancies and those complicated by diabetes (overnutrition; fetal macrosomia) and preeclampsia (fetal growth restriction; high sheer stress; reduced nutrient transport; reduced eNOS). Using confocal microscopy and in situ mass spectroscopy, the glycocalyx coverage will be correlated with fetal growth and maternal complications. An ex vivo perfused placental model will be used to
investigate effects of altered flow on transport of tagged hydrophilic solutes, changes in GLX coverage and composition, altered eNOS and endothelial adhesion molecules. Doppler ultrasound angiography will reveal changes in maternal and fetal blood flows in the placenta. Epigenetic alterations in key genes will be probed.

The data will deliver new knowledge on the role of the placental glycocalyx in regulating nutrient transfer and fetal growth. The impaired mechanisms underlying trans-placental nutrient transfer in different pregnancy complications will be elucidated and lead to novel approaches to alleviating fetal demise and later cardiovascular complications.
References to learn more:
1. M. GOUVERNEUR B. VAN DEN BERG M. NIEUWDORP E. STROES H. VINK Vasculoprotective properties of the endothelial glycocalyx: effects of fluid shear stress. J of Internal Medicine. https://doi.org/10.1111/j.1365-2796.2006.01625.x
2. N. L. Pillinger (2017). Endothelial Glycocalyx: Basic Science and Clinical Implications. Anaesthesia and Intensive Care. https://doi.org/10.1177/0310057X1704500305