Emerging role for dysregulated decidualization in the genesis of preeclampsia

Abstract

In normal human placentation, uterine invasion by trophoblast cells and subsequent spiral artery remodeling depend on cooperation among fetal trophoblasts and maternal decidual, myometrial, immune and vascular cells in the uterine wall. Therefore, aberrant function of anyone or several of these cell-types could theoretically impair placentation leading to the development of preeclampsia. Because trophoblast invasion and spiral artery remodeling occur during the first half of pregnancy, the molecular pathology of fetal placental and maternal decidual tissues following delivery may not be informative about the genesis of impaired placentation, which transpired months earlier. Therefore, in this review, we focus on the emerging prospective evidence supporting the concept that deficient or defective endometrial maturation in the late secretory phase and during early pregnancy, i.e., pre-decidualization and decidualization, respectively, may contribute to the genesis of preeclampsia. The first prospectively-acquired data directly supporting this concept were unexpectedly revealed in transcriptomic analyses of chorionic villous samples (CVS) obtained during the first trimester of women who developed preeclampsia 5 months later. Additional supportive evidence arose from investigations of Natural Killer cells in first trimester decidua from elective terminations of women with high resistance uterine artery indices, a surrogate for deficient trophoblast invasion. Last, circulating insulin growth factor binding protein-1, which is secreted by decidual stromal cells was decreased during early pregnancy in women who developed preeclampsia. We conclude this review by making recommendations for further prospectively-designed studies to corroborate the concept of endometrial antecedents of preeclampsia. These studies could also enable identification of women at increased risk for developing preeclampsia, unveil the molecular mechanisms of deficient or defective (pre)decidualization, and lead to preventative strategies designed to improve (pre)decidualization, thereby reducing risk for preeclampsia development.

Porphyromonas gingivalis strain-dependent inhibition of uterine spiral artery remodeling in the pregnant rat†

“…This process is highly regulated and thought to occur in various stages whereby the integrity of the arterial endothelium and the surrounding vascular smooth muscle layer are disrupted and invaded by extravillous trophoblasts (EVT). The first stage of remodeling begins during decidualization of the uterus and is characterized by disruption of the arterial endothelium and intimal layer and by loss of vascular smooth muscle cells [3,4]. The second stage of remodeling involves invasion of the arterial lumen and the uterine interstitium by EVT [5].…”

“…There is emerging evidence that defective decidualization during early pregnancy can affect EVT invasion and spiral artery remodeling resulting in pregnancy complications that involve DDP [4,6]. A plethora of cytokines within the uterine microenvironment such as IL-1β, IL-6, IL-10, IL-11, IL-15, TNF-α, and the transforming growth factor beta (TGF-β) superfamily including the activins regulate EVT invasion and spiral artery remodeling during normal pregnancy [7][8][9][10][11].…”

Integrative analysis of the forkhead box A2 (FOXA2) cistrome for the human endometrium

“…Uterine glands are also postulated to impact stromal cell decidualization (2), which is essential for pregnancy establishment in humans and rodents (11,12). Recently, defective stromal cell decidualization in early pregnancy was linked to later pregnancy complications such as preeclampsia and miscarriage (13,14). Thus, uterine glands and, by inference, their secretions and products are essential determinants of the embryotrophic potential and functional capacity of the uterus for pregnancy.…”

Immune‑related pathophysiological causes relevant to a subset of patients with preeclampsia (Review)

“…A majority of studies focusing on preeclampsia have shared several overlapping genetic findings on defective decidualization (35,36,40). Abnormal decidualization leads to a decreased EVT invasion and to the development of preeclampsia, which corroborates the concept of the endometrial antecedents of preeclampsia (40,41).…”