Decidual Hemostasis, Inflammation, and Angiogenesis in Pre-Eclampsia

 

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ABSTRACT

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.

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Frederick SchatzPh.D. 

Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine

333 Cedar Street, LSOG room 409, New Haven, CT 06510

Email: frederick.schatz@yale.edu