Plasminogen activators and plasminogen activator inhibitors in endometriosis

Abstract

Endometriosis is one of the most frequent benign gynecological diseases that affect women. Little is known about the pathogenesis and etiology of endometriosis, despite the numerous studies performed in this field. Although endometriosis is a benign disease, the endometrial tissue, after attachment to the peritoneum, has the ability to grow and invade the surrounding tissues. Similar to neoplastic growth, local extracellular proteolysis might take place, and therefore, the fibrinolytic system may be involved. An altered expression of several components of the fibrinolytic system in the endometrium and peritoneal fluid of women with the disease has been suggested as a key factor in the establishment of the endometriotic lesions. There is evidence of increased fibrinolytic activity in the eutopic endometrium of these women, resulting in endometrial fragments with a high potential to degrade the extracellular matrix and facilitate implantation. The peritoneum possesses an inherent fibrinolytic activity that is responsible for the degradation of the fibrin deposits originated after an injury. This physiological function allows a correct repair of the mesothelium, and therefore, prevents the formation of adhesions. Peritoneal fluid of women with endometriosis and pelvic adhesions has shown to have an increased fibrinolytic activity that may be implicated in reducing the formation of new adhesions. Endometriotic tissue has abnormal proteolytic capacity, which is determined by modifications of the fibrinolytic parameters in this tissue. Proteolytic status is determined by the imbalance between plasminogen activators and plasminogen activator inhibitors, which are expressed differently depending on the type of lesion considered and the stage of the disease. The aim of the present study is to review the role of the plasminogen activator system in endometriosis, consider the clinical implications and focus on possible further research efforts and therapeutic applications in this disease.

Peritoneal Fluid Reduces Angiogenesis-Related MicroRNA Expression in Cell Cultures of Endometrial and Endometriotic Tissues from Women with Endometriosis

“…Given that VEGF-A has been shown to induce uPA expression [75], it seemed reasonable to study angiogenic and fibrinolytic systems in our study subjects simultaneously. Furthermore, it has been reported that uPA levels are significantly higher in the endometrium from women with endometriosis than in controls [23], [53], [55], [77]–[79], In the present study, we observed a significant induction of uPA and PAI-1 protein in the stromal cell culture in response to the presence of both peritoneal fluids. Moreover, a significant positive correlation was observed between the changes in VEGF-A and uPA protein levels in control endometrial culture after exposure to peritoneal fluid pools.…”

Peritoneal cytokines and adhesion formation in endometriosis: an inverse association with vascular endothelial growth factor concentration

“…It is widely accepted that development of peritoneal adhesions is related to fibrin deposition, which may be due to abrogation of the fibrinolytic system (10-13, 27, 28). Changes in the fibrinolytic system also have been reported in the peritoneal cavity and endometrioid tissues of endometriosis patients (29)(30)(31)(32)(33). Accordingly, formation of adhesions in course of endometriosis may be facilitated by some inflammatory cytokines such as IL-1 and IL-6 via inhibition of fibrinolysis due to activation of plasminogen activator inhibitor-1 (PAI-1) (28,34,35).…”

PAI‐1 in tissue fibrosis

“…PAI-1 is also implicated in endometriosis where the concentration of PAI-1 is higher compared with healthy endometrium. The elevated PAI-1 may inhibit uPA activity and thus contributes to excess accumulation of collagen and other ECM in endometrium (reviewed in Gilabert-Estelles et al, 2005). Therefore, findings of numerous case studies establish the strong association of abnormal (deficient or elevated) PAI-1 level/activity with a variety of human diseases.…”