Over-expression of the thrombin receptor (PAR-1) in the placenta in preeclampsia: a mechanism for the intersection of coagulation and inflammation

Abstract

Objective: Preeclampsia (PE) is characterized by excessive thrombin generation, which has been implicated in the multiple organ damage associated with the disease. The biological effects of thrombin on coagulation and inflammation are mediated by protease-activated receptor-1 (PAR-1), a G protein-coupled receptor. The aim of this study was to determine whether preterm PE is associated with changes in placental expression of PAR-1.

Study design: This cross-sectional study included two groups matched for gestational age at delivery: (1) patients with preterm PE (<37 weeks of gestation; n = 26) and (2) a control group of patients with preterm labor without intra-amniotic infection (n = 26). Placental tissue microarrays were immunostained for PAR-1. Immunoreactivity of PAR-1 in the villous trophoblasts was graded as negative, weak-positive, or strong-positive.

Results: (1) The proportion of cases with strong PAR-1 immunoreactivity was significantly higher in placentas of patients with PE than in placentas from the control group (37.5% (9/24) vs. 8.7% (2/23); p = 0.036, respectively). (2) PAR-1 immunoreactivity was found in the cellular compartments of the placental villous tree, mainly in villous trophoblasts and stromal endothelial cells. (3) PAR-1 was detected in 92.3% (24/26) of the placentas of women with PE and in 88.5% (23/26) of the placentas from the control group.

Conclusion: Placentas from pregnancies complicated by preterm PE had a significantly higher frequency of strong PAR-1 expression than placentas from women with spontaneous preterm labor. This observation is consistent with a role for PAR-1 as a mediator of the effect of thrombin on coagulation and inflammation in PE. We propose that the effects of thrombin in PE are due to increased thrombin generation and higher expression of PAR-1, the major receptor for this enzyme.

Figure 1

Classification of PAR-1 immunoreactivity in placental tissue microarray sections. Individual cores show variable immunoreactivity: negative (A), weak-positive (B), and strong-positive (C), which was the scale used for the grading of placental immunoreactivity to PAR-1 antibodies in both study groups.

Figure 2

Immunoblotting of placenta, fetal membrane and cell lines PAR-1 expression. Forty micrograms of protein was electrophoreased on a 7.5% SDS-PAGE gel. Proteins were electroblotted after electrophoresis and probed with anti-PAR-1 antibody. Placental tissues express more PAR-1 than fetal membranes in a given placenta and JAR and HTR-8/SVneo cells express readily detectable amounts of PAR-1. P: Placental villous tissue; CD: chorion-decidua; A: amnion; HTR: HTR-8/Svneo cells; C: control protein lysate for PAR-1.