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

人类胎盘是胎儿的重要器官;它保护胎儿免受有害的母体病原体和免疫细胞的侵害，同时将氧气和重要的营养物质从母体输送给胎儿。它是血绒膜的-胎盘绒毛沐浴在母体血液中，可以直接吸收营养（图1a）。这些溶质必须穿过外层合体滋养层和下面的胎儿内皮进入胎儿血液（图1b）。这两层提供了一系列的阻力;病理学导致胎儿生长受损和后来的心血管疾病（疾病的胎儿起源）。Leach实验室的初步研究表明，合体滋养层有一个广泛的糖萼层-潜在的第三层阻力（图1c）。图1a-胎盘绒毛，含有胎儿血管，浸泡在母体血液中;图1b-2层分离母体和胎儿血液;图1c-广泛的糖萼（绿色）覆盖所有胎盘绒毛的外层。注意一些胎儿血管（红色）也有管腔糖萼。在其他系统中，已证明内皮表面糖萼（GLX）层对溶质转运具有较大阻力[1]。GLX携带负电荷，阻止带电溶质。已证明GLX通过eNOS和一氧化氮途径启动血管舒张并改变血流[2]。因此，这个项目将提出的紧迫问题是：胎盘中这一层的功能是什么？它是否阻碍了溶质的运输或过滤了可能通过或不通过的物质？它是否能确保母体血管最大限度地舒张，使胎盘获得最佳的营养输送？为了解决这些问题，该项目将研究正常妊娠和糖尿病（营养过剩;巨大儿）和先兆子痫（胎儿生长受限;高剪切应力;营养转运减少; eNOS减少）并发症的胎盘糖萼的组成。使用共聚焦显微镜和原位质谱，糖萼覆盖率将与胎儿生长和母体并发症相关。将使用离体灌注胎盘模型研究血流改变对标记的亲水性溶质转运、GLX覆盖和组成变化、eNOS和内皮粘附分子改变的影响。多普勒超声血管造影可以显示胎盘中母体和胎儿血流的变化。关键基因的表观遗传学改变将被探测。这些数据将为胎盘糖萼在调节营养转移和胎儿生长中的作用提供新的知识。在不同的妊娠并发症中，经胎盘营养转移的受损机制将被阐明，并导致新的方法来减轻胎儿死亡和随后的心血管并发症。M.古弗诺B。货车登贝格M.尼厄多普湖斯特罗斯·H内皮糖萼的血管保护特性：流体剪切应力的影响。J of Internal Medicine. https://doi.org/10.1111/j.1365-2796.2006.01625.x2. N. L. Pillinger（2017）.内皮糖萼：基础科学和临床意义。麻醉和重症监护。https://doi.org/10.1177/0310057X1704500305

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 toinvestigate 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.x2. N. L. Pillinger (2017). Endothelial Glycocalyx: Basic Science and Clinical Implications. Anaesthesia and Intensive Care. https://doi.org/10.1177/0310057X1704500305