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. 2006 Apr 15;107(8):3173-80.
doi: 10.1182/blood-2005-10-4111. Epub 2005 Dec 27.

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

Rashmi Sood  1 , Shawn Kalloway, Alan E Mast, Cecilia J Hillard, Hartmut Weiler
Affiliations

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

Rashmi Sood et al. Blood. .

Abstract

Humans and rodents exhibit a peculiar type of placentation in which zygote-derived trophoblast cells, rather than endothelial cells, line the terminal maternal vascular space. This peculiar aspect of the placental vasculature raises important questions about the relative contribution of fetal and maternal factors in the local control of hemostasis in the placenta and how these might determine the phenotypic expression of thrombophilia-associated complications of pregnancy. Using genomewide expression analysis, we identify a panel of genes that determine the ability of fetal trophoblast cells to regulate hemostasis at the fetomaternal interface. We show that spontaneous differentiation of trophoblast stem cells is associated with the acquisition of an endothelial cell-like thromboregulatory gene expression program. This program is developmentally regulated and conserved between mice and humans. We further show that trophoblast cells sense, via the expression of protease activated receptors, the presence of activated coagulation factors. Engagement of these receptors results in cell-type specific changes in gene expression. Our observations define candidate fetal genes that are potential risk modifiers of maternal thrombophilia-associated pregnancy complications and provide evidence that coagulation activation at the fetomaternal interface can affect trophoblast physiology altering placental function in the absence of frank thrombosis.

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Figures

Figure 1.
Figure 1.
Cluster display of expression data from TS and DT cells. Entire data set from MGU74Av2 chips (A) or hemostasis related probe sets (B) is represented. Rows represent data for each probe set; columns represent experiments. Expression values are normalized to the median of all measurements for a probe set. Below median value are colored green (down-regulated); above median value are colored red (up-regulated); median values (unchanged) are colored black. Lighter colors reflect probe sets with lower median expression values. Black, white, and gray boxes represent present, absent, and marginal expression status of probe sets in DT cells. The vertical bar in panel A indicates a cluster of genes up-regulated during trophoblast differentiation. This cluster contains 16 hemostasis-related genes highlighted by the vertical bar in panel B. Horizontal marks to the right of panel A indicate the position of hemostasis-related genes.
Figure 2.
Figure 2.
Expression of coagulation-related genes in TS and DT cells and in E8.5 microdissected placenta and embryos determined by semiquantitative RT-PCR. Placenta consisting of trophoblast shell were carefully peeled from the surrounding decidual tissue and separated from Reichert's membrane, visceral yolk sac, and the embryo proper. Dihydrofolate reductase (DHFR; housekeeping gene) and fibroblast growth factor 4 (FGF4; expressed only by the embryo) were included as controls.
Figure 3.
Figure 3.
In situ hybridization analysis of PC, PS, CD39, PN1, TFPI, EPCR, 3-OST1, Par1, and Par4 in E9.5 mouse placenta. TGC indicates trophoblast giant cells; SP, spongiotrophoblast cell layer; and LB, labyrinth. TFPI, EPCR, 3-OST1, and PAR4 are expressed in TGC of E9.5 placenta. CD39 expression is observed in TGC and spongiotrophoblasts. PC is expressed in all 3 trophoblast layers. PS, PN1, and PAR1 are expressed in spongiotrophoblast cells. PAR1 expression extends to the labyrinth with staining in fetal blood cells. Bar represents 0.1 mm.
Figure 4.
Figure 4.
Protease-activated receptor activity in mouse trophoblast cells. Panel A shows real-time changes in intracellular calcium levels in response to thrombin (10 nM), peptide agonists for PAR1 (TRAP1, 100 μM), PAR2 (TRAP2, 100 μM), and PAR4 (TRAP4; 100 uM) in DT cells. Arrows indicate time of addition of the agonist. Bar represents 100 seconds. No change in intracellular calcium level was observed with scrambled peptides. Panel B shows Egr1, Fos, Cyr61, and Ctgf mRNA induction in mouse trophoblast cells determined by real-time PCR analysis of DT cells stimulated with TRAP1, TRAP2, or TRAP4 for 45 minutes. Transcript abundance was normalized to GAPDH and expressed as fold change over average abundance in unstimulated cells. *Statistically significant (P < .05) fold changes.
Figure 5.
Figure 5.
In situ hybridizations on first trimester human placenta. In situ hybridizations on first trimester human placenta showing EPCR (A), CD39 (B), and PN1 (C) expression on trophoblast cells. Panel D shows negative stain with sense control. Bar represents 0.05 mm. EPCR and CD39 are expressed on cytotrophoblast-synctiotrophoblast bilayers of placental villi. PN1 is expressed at a different site on columns of cytotrophoblast cells.
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