Down-regulation of endothelial protein C receptor promotes preeclampsia by affecting actin polymerization.

Preeclampsia is a severe pregnancy-related disease that is found in 3%-5% of pregnancies worldwide and is primarily related to the decreased proliferation and invasion of trophoblast cells and abnormal uterine spiral artery remodelling. However, studies on the pathogenesis of placental trophoblasts are insufficient, and the aetiology of PE remains unclear. Here, we report that endothelial protein C receptor (EPCR), a transmembrane glycoprotein, was down-regulated in placentas from preeclamptic patients. Moreover, lack of EPCR significantly reduced the trophoblast cell proliferation, invasion and tube formation capabilities. Microscale thermophoresis analysis showed that EPCR directly bound to protease-activated receptor 1 (PAR-1), a G protein-coupled receptor. This change resulted in a substantial reduction in active Rac1 and caused excessive actin rearrangement. Our findings reveal a previously unidentified role of EPCR in the regulation of trophoblast proliferation, invasion and tube formation through promotion of actin polymerization, which is required for normal placental development.

Resistin impairs activation of protein C by suppressing EPCR and increasing SP1 expression.

Endothelial cells are vital to blood coagulation and maintain whole body hemostasis. Binding of endothelial cells to endothelial protein C receptor (EPCR) and thrombomodulin (TM) is essential to the formation of activated protein C (APC), one of the key factors regulating blood coagulation. In our study, we showed that resistin, an adipocyte hormone, suppresses thrombin-induced protein C activation in endothelial cells. Resistin treatment results in a reduction in EPCR expression, but not TM. Mechanistically, we demonstrate that resistin induces expression of the nuclear transcription factor SP-1, which could lead to downregulation of EPCR. Both inhibition and silencing of SP1 protein abolishes abnormal APC generation induced by resistin. Collectively, our data support a new role of resistin in disturbing APC formation.

Human platelets express endothelial protein C receptor, which can be utilized to enhance localization of factor VIIa activity.

Essentials Factor VIIa binds activated platelets to promote hemostasis in hemophilia patients with inhibitors. The interactions and sites responsible for platelet-FVIIa binding are not fully understood. Endothelial cell protein C receptor (EPCR) is expressed on activated human platelets. EPCR binding enhances the efficacy of a FVIIa variant and could impact design of new therapeutics. SUMMARY: Background High-dose factor VIIa (FVIIa) is routinely used as an effective bypassing agent to treat hemophilia patients with inhibitory antibodies that compromise factor replacement. However, the mechanism by which FVIIa binds activated platelets to promote hemostasis is not fully understood. FVIIa-DVQ is an analog of FVIIa with enhanced tissue factor (TF)-independent activity and hemostatic efficacy relative to FVIIa. Our previous studies have shown that FVIIa-DVQ exhibits greater platelet binding, thereby suggesting that features in addition to lipid composition contribute to platelet-FVIIa interactions. Objectives Endothelial cell protein C receptor (EPCR) also functions as a receptor for FVIIa on endothelial cells. We therefore hypothesized that an interaction with EPCR might play a role in platelet-FVIIa binding. Methods/results In the present study, we used flow cytometric analyses to show that platelet binding of both FVIIa and FVIIa-DVQ is partially inhibited in the presence of excess protein C or an anti-EPCR antibody. This decreased binding results in a corresponding decrease in the activity of both molecules in FXa and thrombin generation assays. Enhanced binding to EPCR was sufficient to account for the increased platelet binding of FVIIa-DVQ compared with wild-type FVIIa. As EPCR protein expression has not previously been shown in platelets, we confirmed the presence of EPCR in platelets using immunofluorescence, flow cytometry, immunoprecipitation, and mass spectrometry. Conclusions This work represents the first demonstration that human platelets express EPCR and suggests that modulation of EPCR binding could be utilized to enhance the hemostatic efficacy of rationally designed FVIIa analogs.

Prevalence of protein C receptor (PROCR) is associated with inferior clinical outcome in Breast invasive ductal carcinoma.

Recently, PROCR is reported to play an important role in cell growth, apoptosis, proliferation and tumor relapse. Some researchers thought that PROCR+ cells had cancer stem cell ability, which might contribute to progressive behavior in breast cancer. Our study was to assess the expression of PROCR in invasive ductal carcinoma tissues with their prognostic implications. We enrolled formalin fixed paraffin-embedded tumor tissues of 271 patients diagnosed as invasive ductal breast cancer with clinical stage II or III into our study. Immunohistochemistry staining was performed on all the tissue microarray slides, and result were interpreted by two pathologists with blinded method. We analyzed PROCR expression levels with the clinical characteristics as well as their prognostic values. PROCR expression detected in the cell was interpreted. Chi-square test showed us its positive expression had a close association with distant metastases (p=0.035). Univariate survival analysis indicated that prevalence of PROCR expression in the invasive ductal breast cancer was significantly related with decreased disease-free survival (pDFS=0.010) and overall survival (pOS=0.008). In multivariate survival by Cox proportional hazard model, positive expression group for PROCR was found to have shorter DFS [pDFS=0.028, hazard ratio (95% CI): 1.183(1.069-3.140)]. Our findings suggested that breast cancer patients with expression of PROCR is more prone to suffer from distant metastasis and bad clinical outcomes.