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During extravascular trophoblast (EVT) invasion of the decidua, thrombin generated from decidual cell–expressed tissue factor (TF) forms a “hemostatic envelope” that protects against hemorrhage during the initial breaching of capillaries by EVTs and subsequent invasion and remodeling of the spiral arteries and arterioles. Preeclampsia, the world's leading cause of fetal and maternal morbidity and mortality, stems from shallow trophoblast invasion leading to incomplete vascular remodeling that impairs uteroplacental blood flow. A considerable subset of cases of preeclampsia is associated with decidual hemorrhage and maternal thrombophilias, which form excess thrombin from decidual cell–expressed TF. Thrombin affects several cell functions by binding to protease-activated receptors. In first-trimester decidual cells, thrombin enhances expression of sFlt-1, which can block the angiogenic effects of vascular endothelial growth factor (VEGF) and placental growth factor. By contrast, thrombin does not affect decidual cell VEGF expression. Thrombin-enhanced sFlt-1 expression by decidual cells, the predominant cell type encountered by invading cytotrophoblasts, could promote preeclampsia by interfering with angiogenesis-dependent vascular remodeling to reduce uteroplacental blood flow. [ABSTRACT FROM AUTHOR]

Expression of tissue factor (TF), the primary initiator of hemostasis via thrombin formation, is induced during progesterone (P4)-stimulated decidualization of human endometrial stromal cells (HESCs), and remains elevated in decidualized HESCs of luteal and gestational endometrium. In HESC monolayers, progestins elevate TF mRNA and protein levels and estradiol (E2) plus progestin further enhance TF levels for weeks despite no response to E2 alone. This in vitro model mimics the chronic differential ovarian steroid upregulation of TF levels associated with in vivo decidualization. After incubation of HESCs with E2 plus progestin to elevate TF expression, the antiprogestin RU486 completely reversed this upregulation. Thus, progesterone withdrawal transformed decidualization-associated hemostasis of the luteal phase endometrium to the hemorrhagic milieu of menstruation. Transient transfections with TF promoter constructs containing SP and EGR-1 binding sites before and after inactivation by site-directed mutagenesis revealed that Sp1 mediates basal and progestin-enhanced TF transcriptional activity. Progesterone receptor involvement in TF expression was further confirmed since RU486 was a pure antagonist of progestin-enhanced TF mRNA and protein expression, and progestin-enhanced, but not basal, Sp1-mediated transcriptional activity. Enhanced TF mRNA and protein levels in HESCs require co-incubation with progestin and epidermal growth factor receptor (EGFR) agonist indicating that the EGFR mediates progestin-enhanced TF expression. A peak in the primary angiogenic agent, vascular endothelial growth factor (VEGF) in luteal phase endometrium may be indirectly regulated by P4. Neither E2, nor progestin, nor E2 plus progestin affected VEGF expression in glandular epithelial and stromal cells, whereas thrombin enhanced VEGF mRNA and protein levels in decidualized HESCs, but not in the epithelial cells. Transudation of clotting factors to perivascular decidual cell TF in the luteal phase would generate thrombin, enabling it to act as an autocrine enhancer of VEGF in decidualized HESCs. Abnormal uterine bleeding complicates long-term progestin only contraceptive use. After Norplant administration, endometrial VEGF levels are elevated and TF levels are selectively enhanced in decidualized HESCs at bleeding sites. Over-expressed VEGF causes blood vessels to become leaky, increasing clotting factor access to decidualized HESC-expressed TF to promote feed-forward thrombin and VEGF formation. Since thrombin and VEGF induce angiogenesis via separate endothelial cell receptors, they may synergize to elicit aberrant angiogenesis, and ultimately lead to focal bleeding. [Copyright &y& Elsevier]

Abnormal uterine bleeding is the leading indication for discontinuation of long-term progestin-only contraceptives. Histological sections of endometria from long-term progestin-treated patients display abnormally enlarged blood vessels that are prone to bleed in a nonuniform manner. Because it has been complex to attain patients willing to complete long-term studies, and good quality endometrial tissues have proven difficult to obtain, animal models have been used to obviate this problem. In this review, we describe these models including the guinea pig, an animal model we have previously investigated, to assess the mechanisms involved in abnormal uterine bleeding following long-term progestin-only contraception. [ABSTRACT FROM AUTHOR]

Invasion of the decidua by extravillous trophoblasts (EVTs) is accompanied by thrombin generation from decidual cell (DC)-expressed tissue factor (TF). This TF protects against hemorrhage as EVTs breach capillaries and subsequently invade and remodel spiral arteries and arterioles. Pre-eclampsia (P-EC) is the world's leading cause of fetal and maternal morbidity and mortality. It is associated with decidual hemorrhage and maternal thrombophilias, which form excess thrombin from DCs, and with maternal infections and other inflammatory conditions that are associated with excess expression of the proinflammatory cytokines interleukin (IL)-1 β and tumor necrosis factor (TNF) α. In human first-trimester leukocyte-free DCs, (1) thrombin enhances expression of soluble fms-like tyrosine kinase-1 (sFlt-1), a potent inhibitor of angiogenesis; (2) thrombin, IL-1β and TNF-α increase monocyte-recruiting chemokine expression leading to a macrophage excess in the pre-eclamptic decidua. The pathogenesis of P-EC likely stems from shallow EVT invasion leading to impaired decidual vascular remodeling. The resulting reduced uteroplacental blood flow is associated with a hypoxic placenta, which appears to secrete excess sFlt-1 into the maternal plasma. A regulatory role for DCs in vascular remodeling is indicated because impaired decidual vascular remodeling could stem from an aberrant local antiangiogenic milieu elicited by excess sFlt-1 and/or macrophage-inhibited EVT decidual invasion. [ABSTRACT FROM AUTHOR]