The Role of Decidualization in Regulating Endometrial Hemostasis during the Menstrual Cycle, Gestation, and in Pathological States

Abstract

Progesterone-induced decidualized human endometrial stromal cells form a hemostatic envelope that protects against hemorrhage during invasion of endometrial capillaries by implanting blastocyst-derived cytotrophoblasts (CTs). This hemostatic milieu reflects co-upregulated expression of tissue factor (TF), the primary initiator of hemostasis via thrombin generation and plasminogen activator inhibitor type 1, which inactivates tissue-type plasminogen activator, the primary fibrinolytic agent. During deep invasion of the decidua, CTs breach and remodel spiral arteries and arterioles to produce high-conductance vessels. Shallow invasion results in incomplete vascular transformation and an underperfused fetal - placental unit associated with preeclampsia and intrauterine growth restriction. Decidual hemorrhage and severe thrombophilias elicit aberrant thrombin generation from decidual cell-expressed TF. Such thrombin induces decidual cells to synthesize and secrete soluble fms-like tyrosine kinase-1 (sFlt-1), the matrix metalloproteinases MMP-1 and MMP-3, and the neutrophil chemoattractant interleukin-8. Excess sFlt-1 at the implantation site may inhibit CT invasion by altering the angiogenic factor balance. During abruptions, thrombin-enhanced MMP-1, MMP-3 by decidual cells and neutrophil-derived proteases degrade the decidual and fetal membrane extracellular matrix to promote preterm premature rupture of the membranes. In association with long-term progestin-only contraception, overexpression of decidual cell-derived thrombin promotes aberrant angiogenesis and vessel maintenance to contribute to abnormal uterine bleeding.

Metformin inhibits growth of eutopic stromal cells from adenomyotic endometrium via AMPK activation and subsequent inhibition of AKT phosphorylation: a possible role in the treatment of adenomyosis

“…Metformin also has beneficial effects on endometrial abnormalities, such as hyperplasia and cancerous lesions (Palomba et al 2009). Expression of the insulin receptor gene is regulated during the menstrual cycle, enabling insulin to inhibit stromal cell decidualization (Lockwood et al 2007). Recent evidence suggested that metformin inhibits hepatic gluconeogenesis by inhibiting mitochondria complex I activity (Owen et al 2000) and activating its downstream target, AMPK, which can regulate multiple signaling pathways controlling cell proliferation.…”

Placental vascular pathology and increased thrombin generation as mechanisms of disease in obstetrical syndromes

“…While preterm PROM is associated with the activation of the decidua and the membranes, myometrial activation is the major component of preterm labor with intact membranes 58 . This is relevant because the decidua and the membranes have a high TF concentration 17,18,59 . In summary, the evidence brought herein suggests that increased thrombin generation in patients with the great obstetrical syndromes may reflect the activation of the coagulation cascade mainly through the extrinsic arm.…”

Thrombophilia in Assisted Reproductive Technology — Place and Needs of Thromboprophylaxis

“…During this deep invasion step, EVT opened and remodelled spiral arteries and arterioles to produce high-conductance vessels, necessary for the further developing fetus. The haemostasis into decidua during vessel invasion was ensured by up-regulation of tissue factor (TF) and activation of extrinsic coagulation cascade, and simultaneously increased PAI-1 activity [41]. The result of increased TF activity is generation of thrombin.…”

“…The result of increased TF activity is generation of thrombin. In cases of increased thrombin production, such as in inherited thrombophilias conditions, the decidual cells produced anti-angiogenic soluble fmslike tyrosine kinase-1 factor (sFlt-1), which inhibits enzymes related with EVT invasion [41]. Insufficient shallow invasion of ECT into decidua results in incomplete vascular transformation and underperfused embryonic cells, which could lead to early pregnancy loss.…”

“…The serine protease thrombin is a key element in fibrin accumulation [23]. In presence of increased amount of thrombin the decidual cells produce anti-angiogenic soluble fms-like tyrosine kinase-1 factor, which inhibits enzymes related with EVT proliferation [41]. Thus in early pregnancy, thrombin may act as an autocrine/ paracrine enhancer of sFlt-1 expression on the decidual cells to promote implantation failure by interfering with local vascular transformation [64].…”