Plasminogen Activator Inhibitor‐1 4G/5G Polymorphism is Associated with Reproductive Failure: Metabolic, Hormonal, and Immune Profiles

Abstract

PAI-1 4G/5G polymorphism plays a major role in the pathogenesis of RPL and RIF by altering metabolic and immunological profiles.

Polymorphisms of Plasminogen Activator Inhibitor-1 4G/5G, Coagulation Factor XIII Val34Leu and Angiotensin Converting Enzyme I/D Impact on Recurrent Implantation Failure

“…This result agrees with another study which has detected an increased incidence of the 4G allele and/or 4G/4G genotype among the patients with RPL [10]. Moreover, the prevalence of homozygous PAI-1 4G/4G polymorphism was demonstrated to be higher in patients with RIF and RPL [19]. It was also reported that low molecular weight heparin and metformin have been demonstrated to improve implantation process and ameliorate pregnancy complications in patients with 4G/4G genotype because of the hypofibrinolytic impact of overexpressed PAI-1 on implantation [20].…”

Optimization of lentiviral transduction parameters and its application for CRISPR-based secretome modification of human endometrial mesenchymal stem cells

“…PAI-1 expression by decidual cells has been reported to play a decisive role in regulating proteolysis, migration of endothelial cells, and remodeling of maternal tissue during human implantation [27,28,30,31]. Any disturbance in PAI-1 levels may lead to various pregnancy complications, including recurrent pregnancy losses, preeclampsia, intrauterine growth restriction, endometriosis and polycystic ovary syndrome, and unrestricted trophoblastic invasion leading to placenta accrete [30][31][32][33]. Since rhythmicity in PAI-1 expression and secretion levels must exist at varied intervals to maintain pregnancy till term, in the context of possible hMESCs secretome application, both overexpression and knockout of PAI-1 may have sense, depending on nature and stage of the disease supposed to be cured.…”

Genetic and epigenetic variations associated with idiopathic recurrent pregnancy loss

“…On the other hand, studies have shown the importance of genes that control the fibrinolysis process (degradation of fibrin by plasmin enzyme, leading to the dilution of thrombus), such as the plasminogen activator inhibitor-1 (PAI-1) gene that impedes fibrinolysis through inhibition of the enzymes involved in the conversion of plasminogen to plasmin. Several studies have reported an association between the PAI-1 rs1799889 (4G/5G) polymorphism and iRPL, because this polymorphism can generate high levels of its protein and increase resistance to fibrinolysis [45,50,[52][53][54]55]. Salazar et al showed that this genetic variant can alter the metabolic and immunological profiles of patients with iRPL [54].…”

“…Several studies have reported an association between the PAI-1 rs1799889 (4G/5G) polymorphism and iRPL, because this polymorphism can generate high levels of its protein and increase resistance to fibrinolysis [45,50,[52][53][54]55]. Salazar et al showed that this genetic variant can alter the metabolic and immunological profiles of patients with iRPL [54]. Although a meta-analysis of this polymorphism conducted by Su et al failed to find an association with iRPL, the authors suggested that it was due to the high heterogeneity of the studies and emphasized the importance of PAI-1 in the fibrinolysis process, not only in the removal of thrombus but also in the processes of tissue remodeling during embryo implantation and placentation [57].…”