Disrupted PGR-B and ESR1 signaling underlies defective decidualization linked to severe preeclampsia

Abstract

Background:Decidualization of the uterine mucosa drives the maternal adaptation to invasion by the placenta. Appropriate depth of placental invasion is needed to support a healthy pregnancy; shallow invasion is associated with the development of severe preeclampsia (sPE). Maternal contribution to sPE through failed decidualization is an important determinant of placental phenotype. However, the molecular mechanism underlying the in vivo defect linking decidualization to sPE is unknown.Methods:Global RNA sequencing was applied to obtain the transcriptomic profile of endometrial biopsies collected from nonpregnant women who suffer sPE in a previous pregnancy and women who did not develop this condition. Samples were randomized in two cohorts, the training and the test set, to identify the fingerprinting encoding defective decidualization in sPE and its subsequent validation. Gene Ontology enrichment and an interaction network were performed to deepen in pathways impaired by genetic dysregulation in sPE. Finally, the main modulators of decidualization, estrogen receptor 1 (ESR1) and progesterone receptor B (PGR-B), were assessed at the level of gene expression and protein abundance.Results:Here, we discover the footprint encoding this decidualization defect comprising 120 genes—using global gene expression profiling in decidua from women who developed sPE in a previous pregnancy. This signature allowed us to effectively segregate samples into sPE and control groups. ESR1 and PGR were highly interconnected with the dynamic network of the defective decidualization fingerprint. ESR1 and PGR-B gene expression and protein abundance were remarkably disrupted in sPE.Conclusions:Thus, the transcriptomic signature of impaired decidualization implicates dysregulated hormonal signaling in the decidual endometria in women who developed sPE. These findings reveal a potential footprint that could be leveraged for a preconception or early prenatal screening of sPE risk, thus improving prevention and early treatments.Funding:This work has been supported by the grant PI19/01659 (MCIU/AEI/FEDER, UE) from the Spanish Carlos III Institute awarded to TGG. NCM was supported by the PhD program FDGENT/2019/008 from the Spanish Generalitat Valenciana. IMB was supported by the PhD program PRE2019-090770 and funding was provided by the grant RTI2018-094946-B-100 (MCIU/AEI/FEDER, UE) from the Spanish Ministry of Science and Innovation with CS as principal investigator. This research was funded partially by Igenomix S.L.

Genetic Risk Factors Associated With Preeclampsia and Hypertensive Disorders of Pregnancy

“…Many of the genes next to the lead single-nucleotide variants of our study are involved in placental development and function, which are often compromised in preeclampsia. Both genes closest to the lead variant in the locus 11q22, PGR and TRPC6 , are known to affect placental functions and maintenance of pregnancy . PGR has been suggested to contribute to balanced hormonal signaling during pregnancy and subsequently aid the immune and endothelial cells in the cytotrophoblast invasion .…”

GWAS of preeclampsia and hypertensive disorders of pregnancy uncovers genes related to cardiometabolic, endothelial and placental function

“…Both of the genes closest to the lead variant in the locus 11q22, PGR and TRPC6 , as well as NFIL3 on 9q22, are known to affect placental functions and maintenance of pregnancy, as described earlier. PGR has been suggested to contribute to balanced hormonal signalling during pregnancy, and subsequently aid the immune and endothelial cells in the cytotrophoblast invasion 56 . Also the 19q13 located ACTN4 is known for regulating the trophoblast proliferation and differentiation during early pregnancy.…”

“…PGR mediates the effects of progesterone, an essential hormone in pregnancy that maintains pregnancy and promotes endometrial maturation, angiogenesis, vasodilation and placentation 55 . Transcriptomic profiling has revealed perturbed PGR signalling in the decidual endometrium of previously preeclamptic women 56 . The eQTL data provide some support for the causativity of the PGR gene.…”

Two-Dimensional Ultrasound and Triplane Tissue Doppler Ultrasound of Patients with Severe Preeclampsia

“…Ultrasonography is widely used in clinical diagnosis due to its noninvasiveness, low radiation, and simple operation [ 17 ]. The clinical symptoms of SPE are more severe, so the impact on the cardiovascular system is more significant [ 18 ]. Two-dimensional ultrasound and triplane TDI ultrasound were used to analyze the clinical characteristics of SPE patients and the changes in morphology and function indexes of LV and RV.…”