Fetomaternal cross talk in the placental vascular bed: control of coagulation by trophoblast cells

Abstract

IntroductionIn the hemochorial type of placentation observed in humans and mice, fetal nutrition involves the direct uptake of nutrients by zygote-derived trophoblast cells from circulating maternal blood. The required placental morphology is achieved through a highly regulated process of trophoblast differentiation coupled with remodeling of maternal and fetal vasculature. As a consequence, in contrast to all other vascular beds in which the blood vessel endothelium is the principal gatekeeper between tissue and blood, the terminal vascular space of the placenta is lined by trophoblast cells. 1,2 Trophoblast cells are genetically distinct from the maternal vascular endothelium and are derived from a different developmental lineage than endothelial cells. 3 In all nonplacental vascular beds, normal endothelium proactively suppresses the activity of the coagulation system, thereby maintaining a nonthrombogenic surface. A survey of existing data suggests that trophoblast cells also produce endothelial regulators of hemostasis, such as thrombomodulin (TM), endothelial protein C receptor (EPCR), and tissue factor pathway inhibitor (TFPI). [4][5][6][7][8] Such findings indicate that trophoblast cells might exhibit an endothelial cell-like ability to partake in the regulation of hemostasis at the fetomaternal interface. Indeed, the term "endothelial mimicry" has been coined to describe a process of remodeling of the maternal arteries, during which so-called "endovascular" trophoblast cells replace the maternal endothelium in these blood vessels and switch their expression from epithelial to endothelial adhesion receptor repertoire. [9][10][11] It is unknown whether trophoblast cells acquire anticoagulant gene expression in a temporally and spatially controlled manner similar to that described for the subset of endovascular trophoblast cells or whether the acquisition of an endothelial cell-like anticoagulant phenotype is a cell type-defining feature of trophoblast cells in general.The placenta also is a rich source of the initiator of coagulation, tissue factor (TF). TF antigen and procoagulant activity are detected in mouse giant and labrynthine trophoblasts and on human syncytiotrophoblast membranes. [12][13][14][15] With the exception of angiogenic endothelium, and in endothelium subjected to inflammatory and thrombotic stimuli, TF expression is strictly excluded from endothelial cells. Proinflammatory cytokines, ligands for Tollreceptors, and the principal coagulation protease, thrombin, induce TF expression in cultured endothelial cells, evoke increased production of endothelial-leukocyte adhesion receptors, and simultaneously suppress the expression of anticoagulant gene products. This transition from a noncoagulant and antiadhesive phenotype to a state of enhanced coagulation and leukocyte interactions has been termed "endothelial activation" and appears to reflect a principal switch in a concerted gene-expression program. 16 In contrast, trophoblast cells constitutively express TF, thus exhibiting, even under ...

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“…22 Moreover, unlike all other vascular beds, the maternal endothelium is replaced by trophoblast which expresses thromboregulatory proteins. 23 Thrombin and other coagulation proteases provide signals mediated through protease-activated receptors (PARs) transforming extravillous trophoblast into an invasive phenotype. 24 Conditions within the developing placenta are thus ripe for coagulation and fibrin deposition.…”

Role of Hypoxia-Inducible Transcription Factors 1α and 2α in the Regulation of Plasminogen Activator Inhibitor-1 Expression in a Human Trophoblast Cell Line

“…Successful placentation and maintenance of pregnancy requires that invasive and hemostatic processes in trophoblasts are tightly regulated [1][2][3][4]. The plasmin/plasminogen activator system plays a key role in modulating these pathways at the maternal-fetal interface [2,3].…”

“…The plasmin/plasminogen activator system plays a key role in modulating these pathways at the maternal-fetal interface [2,3]. In trophoblasts as in other cell types, plasmin-dependent fibrinolysis is controlled through the action of tissue-type plasminogen activator (tPA), whereas urokinase-type plasminogen activator (uPA) mediates plasmin-associated degradation of the extracellular matrix, a requisite for cellular invasion [5,6].…”

Placental vascular pathology and increased thrombin generation as mechanisms of disease in obstetrical syndromes

“…The networks of the placental vascular tree either on the maternal or fetal side are dynamic structures that can be substantially altered in cases of abnormal placentation and trophoblast invasion. The human trophoblast has properties of endothelial cells and can regulate the degree of activation of the coagulation cascade in the intervillous space 97,98 .…”