Involvement of human decidual cell-expressed tissue factor in uterine hemostasis and abruption

Abstract

Vascular injury increases access and binding of plasma-derived factor VII to perivascular cell membrane-bound tissue factor (TF). The resulting TF/VIIa complex promotes hemostasis by cleaving pro-thrombin to thrombin leading to the fibrin clot. In human pregnancy, decidual cell-expressed TF prevents decidual hemorrhage (abruption). During placentation, trophoblasts remodel decidual spiral arteries into high conductance vessels. Shallow trophoblast invasion impedes decidual vascular conversion, producing an inadequate uteroplacental blood flow that elicits abruption-related placental ischemia. Thrombin induces several biological effects via cell surface protease activated receptors. In first trimester human DCs thrombin increases synthesis of sFlt-1, which elicits placental ischemia by impeding angiogenesis-related decidual vascular remodeling. During pregnacy, the fibrillar collagen-rich amnion and choriodecidua extracellular matrix (ECM) provides greater than additive tensile strength and structural integrity. Thrombin acts as an autocrine/paracrine mediator that degrades these ECMs by augmenting decidual cell expression of: 1) matrix metalloproteinases and 2) interleukin-8, a key mediator of abruption-associated decidual infiltration of neutrophils, which express several ECM degrading proteases. Among the cell types at the maternal fetal interface at term, TF expression is highest in decidual cells indicating that this TF meets the hemostatic demands of labor and delivery. TF expression in cultured term decidual cells is enhanced by progestin and thrombin suggesting that the maintenance of elevated circulating progesterone provides hemostatic protection and that abruption-generated thrombin acts in an autocrine/paracrine fashion on decidual cells to promote hemostasis via enhanced TF expression.

Figure 1. Immunohistochemical analysis of tissue factor (TF) expression at the decidual/placental interface

Serial sections of decidual basalis were immunostained for TF and vimentin in an idiopathic preterm specimen (A: TF, and B: vimentin). Decidual cells (DCs) (arrows), identified by positive vimentin staining, exhibited strong peri-membranous TF staining. TF staining was virtually absent in interstitial trophoblast (arrowheads). Similar results were seen in term specimens (C). Placental villi exhibited moderate TF staining in the mesoderm (“M”), where the staining was primarily localized to peri-vascular adventitia (small arrows), as shown in a preterm specimen (D). Syncytiotrophoblast (“S”) and cytotrophoblast (“C”) exhibited no TF immunostaining. Similar results were seen in term specimens (not shown). Negative control immunostaining using a nonspecific isotype-matched antibody revealed no positive signals (E). A histogram of the HSCORE (mean ± SEM) of the intensity of TF immunostaining indicates highest staining in DCs (*, vs. interstitial trophoblast and the villous mesoderm of the same specimen group, P<0.05), with moderate staining in the villous mesoderm (†, vs. interstitial trophoblast in the same specimens, P<0.05) (F) [see(22)].

Figure 2. Effects of MPA and thrombin on TF expression in decidual cells (DCs)

Confluent leukocyte-free term DCs, were primed in E₂ or E₂ + MPA then switched to a serum-free defined medium (DM) with corresponding steroids ± 2.5 U/ml thrombin (Th) for 24 hr. ELISAs were performed for TF in cell lysates with the results normalized to total cell protein: n=10 (mean ± SEM). * vs. E₂; ** vs. E₂+MPA and E₂ + Th; p<0.05. [see (22)].