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Bioinformatics approach reveals evidence for impaired endometrial maturation before and during early pregnancy in women who developed preeclampsia - PubMed

Comparative Study

Bioinformatics approach reveals evidence for impaired endometrial maturation before and during early pregnancy in women who developed preeclampsia

Maria B Rabaglino et al. Hypertension. 2015 Feb.

Erratum in

  • Correction.

    [No authors listed] [No authors listed] Hypertension. 2015 Jun;65(6):e46-7. doi: 10.1161/HYP.0000000000000027. Hypertension. 2015. PMID: 25972563 No abstract available.

Abstract

Impaired uterine invasion by extravillous trophoblast in early gestation is implicated in the genesis of preeclampsia, a potentially lethal malady of human pregnancy. However, reasons for extravillous trophoblast dysfunction remain unclear because of virtual inaccessibility of early placental and uterine tissues from women who develop preeclampsia, and the absence of animal models in which the disease spontaneously occurs. Consequently, the possibility that deficient or defective maturation of the endometrium (decidualization) may compromise extravillous trophoblast invasion in preeclampsia remains unexplored. Using a bioinformatics approach, we tested this hypothesis identifying 396 differentially expressed genes (DEG) in chorionic villous samples from women at ≈11.5 gestational weeks who developed severe preeclampsia symptoms 6 months later compared with chorionic villous samples from normal pregnancies. A large number, 154 or 40%, overlapped with DEG associated with various stages of normal endometrial maturation before and after implantation as identified by other microarray data sets (P=4.7×10(-14)). One-hundred and sixteen of the 154 DEG or 75% overlapped with DEG associated with normal decidualization in the absence of extravillous trophoblast, ie, late-secretory endometrium (LSE) and endometrium from tubal ectopic pregnancy (EP; P=4.2×10(-9)). Finally, 112 of these 154 DEG or 73% changed in the opposite direction in microarray data sets related to normal endometrial maturation (P=0.01), including 16 DEG upregulated in decidual (relative to peripheral blood) natural killer cells that were downregulated in chorionic villous samples from women who developed preeclampsia (P<0.0001). Taken together, these results suggest that insufficient or defective maturation of endometrium and decidual natural killer cells during the secretory phase and early pregnancy preceded the development of preeclampsia.

Keywords: decidualization; endometrial cycle; natural killer cell; pregnancy; trophoblast.

© 2014 American Heart Association, Inc.

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Figures

Figure 1
Figure 1. Clusters of genes induced during pre-decidualization and decidualization in ectopic pregnancy are down-regulated in CVS from preeclamptic women

The Venn Diagrams show significant overlap (*P<0.0001 by Pearson’s chi-square test) between DEG down-regulated in CVS from PE women (PE-CVS; relative to CVS from women with normal pregnancy) and DEG up-regulated in: (A) late-secretory endometrium (LSE; relative to proliferative endometrium; 38 DEG, Table S3A) and (B) EP endometrium with intermediate-decidualization (intDEC) changes (relative to EP endometrium without decidualization changes), which lacks extravillous trophoblast (32 DEG, Table S3B). In (C), there is significant overlap (*P<0.0001) between DEG down-regulated in PE-CVS and DEG up-regulated in LSE and EP endometrium with intermediate-decidualized changes (16 DEG, Table S3C).

Figure 2
Figure 2. Clusters of genes induced during decidualization in intrauterine and ectopic pregnancy are down-regulated in CVS from preeclamptic women

The Venn Diagrams show significant overlap (*P<0.0001 by Pearson’s chi-square test) between DEG down-regulated in PE-CVS relative to CVS from women with normal pregnancy and DEG up-regulated in: (A) intermediate-decidualized endometrium (intDEC; 37 DEG, Table S4A) and (B) confluent-decidualized endometrium (confDEC; 46 DEG, Table S4B) both from IUP (relative to EP endometrium without decidualization changes) and containing extravillous trophoblast. In (C), there are 32 DEG in common between DEG down-regulated in PE-CVS and DEG up-regulated in EP endometrium with intermediate-decidualized changes and without EVT (also see Figure 1B), and 37 DEG in common between DEG down-regulated in PE-CVS and DEG up-regulated in IUP endometrium with intermediate-decidualized changes (EVT present). The majority of these DEG, in turn, are overlapping (30 DEG, Table S4C; *p<0.0001) suggesting minimal EVT contribution to the overlap.

Figure 3
Figure 3. Confluence of gene clusters induced during (pre-) decidualization is down-regulated in CVS from preeclamptic women

There are 20 DEG down-regulated in CVS from PE women (PE-CVS; relative to CVS from women with normal pregnancy) uniquely up-regulated in late-secretory endometrium (LSE, relative to proliferative endometrium). There is also significant overlap (*p<0.0001 by Pearson’s chi-square test) between DEG down-regulated in PE-CVS and DEG up-regulated in EP and IUP endometrium both with intermediate-decidualized (intDEC) changes, and IUP endometrium with confluent-decidualized (confDEC) changes, but not LSE (13 DEG); and in all 4 of the datasets related to different degrees of endometrial maturation (16 DEG). See Table S5 for individual genes and Figure 4 for average expression levels of these genes.

Figure 4
Figure 4. Average gene expression levels (log base 2) in endometrium from different stages of endometrial maturation and CVS from preeclamptic women

(A) Average expression of 20 DEG down-regulated in CVS obtained from women who developed PE (PE-CVS; relative to CVS from women with normal pregnancy) and up-regulated in mid- and late-secretory endometrium (MSE and LSE, respectively; relative to proliferative endometrium, PrE). (B) Average expression of 13 DEG down-regulated in PE-CVS and up-regulated in IUP and EP endometrium with intermediate-decidualized (intDEC) changes, and IUP endometrium with confluent-decidualized (confDEC) changes, but not LSE. (C) Average expression for 16 DEG down-regulated in PE-CVS and upregulated in in all 4 of the datasets related to different degrees of endometrial maturation. (D) Heat map corresponding to Figure 4C. The individual DEG in Figure 4A, B and C are listed in Table S5. EP, ectopic pregnancy; IUP, intrauterine pregnancy; nonDEC, non-decidualized endometrium from EP; ESE, early-secretory endometrium. Significantly different (p<0.05) from: a, PrE; b, ESE; c, MSE; d, LSE; e, intDEC-EP; f, intDEC-IUP; g, nonDEC; h, PE-CVS.

Fig. 5
Fig. 5. Clusters of genes induced in decidual Natural Killer cells are down-regulated in CVS from preeclamptic women

(A) The Venn diagram shows significant overlap (*P<0.0001 by Pearson’s chi-square test) between DEG down-regulated in PE-CVS relative to CVS from women with normal pregnancy and DEG up-regulated in decidual Natural Killer cells (dNK) relative to peripheral blood CD56dim or CD56bright NK cells. The official symbols of the overlapping genes are listed in panel (B).

Figure 6
Figure 6. Five-stage model of placental preeclampsia

Based on a bioinformatics approach, the findings of this study raise the possibility that impaired endometrial maturation and deficient decidual NK cell number and/or function in the secretory phase (pre-decidualization) and during early pregnancy (decidualization) precede the development of preeclampsia. As (pre-) decidualization and associated decidual NK cell function are emerging as important players in successful placentation, perturbation of these biological processes may contribute to the etiology of preeclampsia at least in a subset of women who develop the disease. Preeclampsia may arise in some women with little or no endometrial or placental pathology.

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