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.

Keywords: Decidua; Endometrium; Immune cells; Maternal-fetal interface; Placenta; Trophoblast.

Figure 1

Circulating IGFBP-1 concentrations in normal pregnancy and preeclampsia. (A) Serial measurements of IGFBP-1 were performed throughout pregnancy. IGFBP-1 was significantly reduced in preeclampsia compared to normal pregnancy at 16, 20, and 24 weeks of gestation (p=0.006, p=0.001, and p=0.04, respectively). IGFBP-1 was significantly elevated in preeclampsia at 36 weeks of gestation (p=0.04). (B) Scatterplot of data from 16 gestational weeks shows good separation of data points between the 2 cohorts. Anim-Nyame et al., 2000 with permission.

Figure 2

Average expression levels (log base 2) of differentially expressed genes (DEG) in samples obtained from endometrium at different stages of endometrial maturation and from chorionic villous samples (CVS). PE: preeclampsia; NP-normal pregnancy. PrE, ESE, MSE, LSE: proliferative and early, middle and late secretory endometrium, respectively; IntDEC, ConfDEC and nonDEC: intermediate, confluent and non-decidualized endometrium determined histologically. Significantly different (P<0.05) from: a, PrE; b, ESE; c, MSE; d, LSE; e, intDEC-EP; f, intDEC-IUP; g, nonDEC; *P<0.0001 vs nonpregnant (NP)-CVS. Rabaglino et al., 2015 with permission.

Figure 3

Aberrant decidualization in the late secretory phase and during early pregnancy may play a role in the development of preeclampsia for some women. See text for details.

Figure 4

Composite model of preeclampsia that includes the concept of dysregulated decidual and immune cell function in the genesis of impaired placentation (steps 1–3) prior to the traditional 2 or 3 stage model of disease pathogenesis (steps 4–6).