Altered IRE1α-Dependent Decidual Programming Links Impaired Inflammation and Angiogenesis in Recurrent Implantation Failure.
- 1Laboratorio de Inmunofarmacología, Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales (IQUIBICEN), CONICET, Universidad de Buenos Aires, Buenos Aires C1428EGA, Argentina.
- 2Fertilis Medicina Reproductiva, Buenos Aires B1609JEC, Argentina.
- 3Instituto de Medicina Experimental (IMEX), Buenos Aires C1425AUM, Argentina.
Abstract
Background
Decidualization alters the endometrial stromal cells (EnSC) secretome, allowing sterile inflammation associated with embryo implantation, but mechanisms that lead to alterations in this process are still unknown. We evaluated whether impaired IRE1α-mediated endoplasmic reticulum (ER) stress signalling contributes to defective angiogenic decidual programming in patients with recurrent implantation failure (RIF).Methods
Candidate pathways were identified with bioinformatic analyses of endometrial arrays and validated in endometrial biopsies from fertile and RIF women (secretory phase) by RT-qPCR and in isolated EnSC by flow cytometry. Functional alterations were evaluated using trophoblast spheroid and endothelial cell migration assays. ER stress was pharmacologically induced in EnSC using thapsigargin.Results
RIF endometria displayed impaired in vivo decidualization, with reduced expression of IGFBP1 and PGR, together with altered expression of molecules involved in blastocyst adhesion. Conditioned media from RIF-derived EnSC-impaired trophoblast outgrowth. RIF samples displayed an anti-angiogenic and altered inflammatory profile, characterized by reduced intracellular IL-1β accumulation, decreased VEGFA, and increased sFlt1 expression. Bioinformatic analyses identified IRE1α pathway as a central altered network associated with angiogenesis. Consistently, RIF samples showed reduced expression of IRE1α, sXBP1, and NLRP3. Moreover, ER stress induction in EnSC promoted endothelial cell migration.Conclusions
RIF is associated with defective angiogenic decidual programming linked to impaired IRE1α-mediated ER stress signalling. These findings identify the IRE1α axis as a potential pathway of interest for future therapeutic exploration in recurrent implantation failure.
Related
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BibTeX
@article{castagnola2026altered,
title = {{Altered IRE1α-Dependent Decidual Programming Links Impaired Inflammation and Angiogenesis in Recurrent Implantation Failure.}},
author = {Lara Castagnola and Lourdes Materazzi and Daniel Paparini and Ana Schafir and Marcela Irigoyen and Esteban Grasso and Nancy Charó and Daiana Vota and Agustina Marcial and Diego Gnocchi and Alejandro Gustavo Martínez and Antonio Cattaneo and Lautaro Tessari and Vanesa Hauk and Soledad Gori and Rosanna Ramhorst},
journal = {Biology},
year = {2026},
month = sep,
doi = {10.3390/biology15191693},
url = {https://europepmc.org/article/MED/42883366},
note = {CC BY},
}
RIS
TY - JOUR
TI - Altered IRE1α-Dependent Decidual Programming Links Impaired Inflammation and Angiogenesis in Recurrent Implantation Failure.
AU - Lara Castagnola
AU - Lourdes Materazzi
AU - Daniel Paparini
AU - Ana Schafir
AU - Marcela Irigoyen
AU - Esteban Grasso
AU - Nancy Charó
AU - Daiana Vota
AU - Agustina Marcial
AU - Diego Gnocchi
AU - Alejandro Gustavo Martínez
AU - Antonio Cattaneo
AU - Lautaro Tessari
AU - Vanesa Hauk
AU - Soledad Gori
AU - Rosanna Ramhorst
PY - 2026
DA - 2026/09/23
JO - Biology
DO - 10.3390/biology15191693
UR - https://europepmc.org/article/MED/42883366
AB - Background Decidualization alters the endometrial stromal cells (EnSC) secretome, allowing sterile inflammation associated with embryo implantation, but mechanisms that lead to alterations in this process are still unknown. We evaluated whether impaired IRE1α-mediated endoplasmic reticulum (ER) stress signalling contributes to defective angiogenic decidual programming in patients with recurrent implantation failure (RIF).Methods Candidate pathways were identified with bioinformatic analyses of endometrial arrays and validated in endometrial biopsies from fertile and RIF women (secretory phase) by RT-qPCR and in isolated EnSC by flow cytometry. Functional alterations were evaluated using trophoblast spheroid and endothelial cell migration assays. ER stress was pharmacologically induced in EnSC using thapsigargin.Results RIF endometria displayed impaired in vivo decidualization, with reduced expression of IGFBP1 and PGR, together with altered expression of molecules involved in blastocyst adhesion. Conditioned media from RIF-derived EnSC-impaired trophoblast outgrowth. RIF samples displayed an anti-angiogenic and altered inflammatory profile, characterized by reduced intracellular IL-1β accumulation, decreased VEGFA, and increased sFlt1 expression. Bioinformatic analyses identified IRE1α pathway as a central altered network associated with angiogenesis. Consistently, RIF samples showed reduced expression of IRE1α, sXBP1, and NLRP3. Moreover, ER stress induction in EnSC promoted endothelial cell migration.Conclusions RIF is associated with defective angiogenic decidual programming linked to impaired IRE1α-mediated ER stress signalling. These findings identify the IRE1α axis as a potential pathway of interest for future therapeutic exploration in recurrent implantation failure.
SN - 2079-7737
ER -