Impaired decidual natural killer cell regulation of vascular remodelling in early human pregnancies with high uterine artery resistance

Abstract

During human pregnancy, natural killer (NK) cells accumulate in the maternal decidua, but their specific roles remain to be determined. Decidual NK (dNK) cells are present during trophoblast invasion and uterine spiral artery remodelling. These events are crucial for successful placentation and the provision of an adequate blood supply to the developing fetus. Remodelling of spiral arteries is impaired in the dangerous pregnancy complication pre-eclampsia. We studied dNK cells isolated from pregnancies at 9–14 weeks' gestation, screened by uterine artery Doppler ultrasound to determine resistance indices which relate to the extent of spiral artery remodelling. dNK cells were able to promote the invasive behaviour of fetal trophoblast cells, partly through HGF. Cells isolated from pregnancies with higher resistance indices were less able to do this and secreted fewer pro-invasive factors. dNK cells from pregnancies with normal resistance indices could induce apoptotic changes in vascular smooth muscle and endothelial cells in vitro, events of importance in vessel remodelling, partly through Fas signalling. dNK cells isolated from high resistance index pregnancies failed to induce vascular apoptosis and secreted fewer pro-apoptotic factors. We have modelled the cellular interactions at the maternal-fetal interface and provide the first demonstration of a functional role for dNK cells in influencing vascular cells. A potential mechanism contributing to impaired vessel remodelling in pregnancies with a higher uterine artery resistance is presented. These findings may be informative in determining the cellular interactions contributing to the pathology of pregnancy disorders where remodelling is impaired, such as pre-eclampsia.Copyright © 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Fetal-derived adrenomedullin mediates the innate immune milieu of the placenta

“…Our data clearly demonstrated that the fetal levels and genotype of Adm were the critical determinants of its function at tional differences between placentas of humans and mice (44)(45)(46), the reduction in fetal vascular branching, failed SA remodeling, and lack of SA reendothelialization we describe here have long been associated with preeclampsia in humans (47). More recently, additional studies demonstrating deregulation of uNK cells and the levels of placental chemokines and cytokines have also been appreciated in human preeclampsia (20,22). Finally, some of the most clinically relevant breakthroughs in recent years have been discoveries of numerous angiogenic factors and their soluble receptors as predictive biomarkers of preeclampsia, including soluble Fms-like tyrosine kinase 1 (sFlt1) and soluble endoglin (sEng) (48).…”

“…uNK cells secrete a wide variety of growth factors, chemokines, cytokines, and MMPs (4) and thus represent a major constituent of the innate immune milieu of the placenta. Several recent studies have begun to reveal important pathophysiological roles for uNK cells in human pregnancy (19)(20)(21)(22). However, much remains unknown about the precise molecular interactions between fetal trophoblast cells and uNK cells in the placenta.…”

Sofalcone Upregulates the Nuclear Factor (Erythroid-Derived 2)–Like 2/Heme Oxygenase-1 Pathway, Reduces Soluble fms–Like Tyrosine Kinase-1, and Quenches Endothelial Dysfunction

“…[14][15][16] We investigated whether sofalcone can reduce TNF-α-induced endothelial dysfunction by examining the degree of monocyte adhesion to endothelial cells stimulated with TNF-α (Figure 4). TNF-α-treated HUVECs significantly increased THP-1 monocyte adhesion to HUVECs compared with the control (n=3; P<0.01).…”

Immune regulation at the fetal‐maternal interface with focus on decidual macrophages

“…For instance, they have been shown to be closely associated with remodeling vessels (Smith et al, 2009;Hazan et al, 2010), to promote trophoblast invasion (Hanna et al, 2006;De Oliveira et al, 2010;Fraser et al, 2012) and to stimulate vascular remodeling by the production of angiogenic factors (Hanna et al, 2006;Lash et al, 2006;Kalkunte et al, 2009). The interaction of activating NK cell receptors with MHC I molecules on trophoblast cells seems to promote both chemotactic and angiogenic factors (Hanna et al, 2006), suggesting that a moderate level of activation is necessary for proper trophoblast invasion and spiral artery remodeling.…”

“…Another method may be the use of uterine artery Doppler ultrasound to define first trimester pregnancies with normal or high resistance indices. This measurement reflects the level of spiral artery remodeling and thus the risk of developing complications associated with impaired vascular remodeling, such as preeclampsia (Fraser et al, 2012). However, only an approximation of the risk is obtained and only to a certain group of complications.…”