Role of Plasminogen Activator Inhibitor Type 1 in Pathologies of Female Reproductive Diseases

Abstract

Normal pregnancy is a state of hypercoagulability with diminishing fibrinolytic activity, which is mainly caused by an increase of plasminogen activator inhibitor type 1 (PAI-1). PAI-1 is the main inhibitor of plasminogen activators, including tissue-type plasminogen activator (tPA) and urokinase-type plasminogen activator (uPA). In human placentas, PAI-1 is expressed in extravillous interstitial trophoblasts and vascular trophoblasts. During implantation and placentation, PAI-1 is responsible for inhibiting extra cellular matrix (ECM) degradation, thereby causing an inhibition of trophoblasts invasion. In the present study, we have reviewed the literature of various reproductive diseases where PAI-1 plays a role. PAI-1 levels are increased in patients with recurrent pregnancy losses (RPL), preeclampsia, intrauterine growth restriction (IUGR), gestational diabetes mellitus (GDM) in the previous pregnancy, endometriosis and polycystic ovary syndrome (PCOS). In general, an increased expression of PAI-1 in the blood is associated with an increased risk for infertility and a worse pregnancy outcome. GDM and PCOS are related to the genetic role of the 4G/5G polymorphism of PAI-1. This review provides an overview of the current knowledge of the role of PAI-1 in reproductive diseases. PAI-1 represents a promising monitoring biomarker for reproductive diseases and may be a treatment target in the near future.

Keywords: endometriosis; gestational diabetes mellitus; intrauterine growth restriction; plasminogen activator inhibitor type 1; polycystic ovary syndrome; preeclampsia; recurrent pregnancy losses; trophoblast invasion.

Figure 1

Schematic diagram of fibrinolysis: plasminogen is activated by plasminogen activator (tPA in blood or uPA in tissue), and then converted to plasmin. Then plasmin cleaves fibrin into fibrin-degradation products. Plasminogen activators inhibitors are PAI-1, PAI-2, C1-esterase inhibitor and protease nexin. Plasmin inhibitors are α2-plasmin inhibitor (α2-PI), α2-macroglobulin (α2-MG) and protease nexin. Pro-uPA can be converted to uPA, which is catalyzed by plasmin, the product of plasminogen.

Figure 2

Schematic diagram of PAI-1’s role during trophoblasts invasion. The fetal side of the human placenta mainly includes cytotrophoblasts and syncytiotrophoblasts, and sycytiotrophoblasts are differentiated and fused by cytotrophoblasts. The cytotrophoblasts invade into the maternal side and differentiate into extravillous interstitial trophoblasts, intermediate trophoblasts and endovascular trophoblasts. Among them, extravillous interstitial trophoblasts and endovascular trophoblasts express plasminogen activator inhibitor type 1 (PAI-1). Furthermore, cells from the maternal side take part in trophoblast invasion, such as endometrial stromal cells, decidual cells, macrophages and endothelial cells. Extravillous trophoblast invasion in early pregnancy is precisely controlled by many factors expressed by trophoblasts and maternal cells, where PAI-1 is the main anti-invasive factor. PAI-1 prevents trophoblast invasion by inhibiting extracellular matrix degradation, which leads to fibrin accumulation in the maternal side. PAI-1 may also play a role in remodeling maternal uterine spiral arteries.