Author:
Hennes Aurélie,Devroe Johanna,De Clercq Katrien,Ciprietti Martina,Held Katharina,Luyten Katrien,Van Ranst Nele,Maenhoudt Nina,Peeraer Karen,Vankelecom Hugo,Voets Thomas,Vriens Joris
Abstract
Abstract
Background
Early embryo implantation is a complex phenomenon characterized by the presence of an implantation-competent blastocyst and a receptive endometrium. Embryo development and endometrial receptivity must be synchronized and an adequate two-way dialogue between them is necessary for maternal recognition and implantation. Proteases have been described as blastocyst-secreted proteins involved in the hatching process and early implantation events. These enzymes stimulate intracellular calcium signaling pathways in endometrial epithelial cells (EEC). However, the exact molecular players underlying protease-induced calcium signaling, the subsequent downstream signaling pathways and the biological impact of its activation remain elusive.
Methods
To identify gene expression of the receptors and ion channels of interest in human and mouse endometrial epithelial cells, RNA sequencing, RT-qPCR and in situ hybridization experiments were conducted. Calcium microfluorimetric experiments were performed to study their functional expression.
Results
We showed that trypsin evoked intracellular calcium oscillations in EEC of mouse and human, and identified the protease-activated receptor 2 (PAR2) as the molecular entity initiating protease-induced calcium responses in EEC. In addition, this study unraveled the molecular players involved in the downstream signaling of PAR2 by showing that depletion and re-filling of intracellular calcium stores occurs via PLC, IP3R and the STIM1/Orai1 complex. Finally, in vitro experiments in the presence of a specific PAR2 agonist evoked an upregulation of the ‘Window of implantation’ markers in human endometrial epithelial cells.
Conclusions
These findings provide new insights into the blastocyst-derived protease signaling and allocate a key role for PAR2 as maternal sensor for signals released by the developing blastocyst.
Graphical Abstract
Funder
Research Council of the KU Leuven
Fonds Wetenschappelijk Onderzoek
Publisher
Springer Science and Business Media LLC
Subject
Developmental Biology,Endocrinology,Reproductive Medicine,Obstetrics and Gynecology
Cited by
1 articles.
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