Ion Channels in The Pathogenesis of Endometriosis: A Cutting-Edge Point of View
Department of Woman, Child and General and Specialized Surgery, University of Campania “Luigi Vanvitelli”, 80138 Naples, Italy
Department of Obstetrics and Gynecology, “Filippo Del Ponte” Hospital, University of Insubria, 21100 Varese, Italy
Department of Neuroscience, Reproductive Sciences and Dentistry, School of Medicine, University of Naples Federico II, 80131 Naples, Italy
Author to whom correspondence should be addressed.
Equal contributions (joint first authors).
Int. J. Mol. Sci. 2020, 21(3), 1114; https://doi.org/10.3390/ijms21031114
Received: 30 December 2019 / Revised: 24 January 2020 / Accepted: 5 February 2020 / Published: 7 February 2020
(This article belongs to the Special Issue Endometriosis Research: From Bench to Bedside)
Background: Ion channels play a crucial role in many physiological processes. Several subtypes are expressed in the endometrium. Endometriosis is strictly correlated to estrogens and it is evident that expression and functionality of different ion channels are estrogen-dependent, fluctuating between the menstrual phases. However, their relationship with endometriosis is still unclear. Objective: To summarize the available literature data about the role of ion channels in the etiopathogenesis of endometriosis. Methods: A search on PubMed and Medline databases was performed from inception to November 2019. Results: Cystic fibrosis transmembrane conductance regulator (CFTR), transient receptor potentials (TRPs), aquaporins (AQPs), and chloride channel (ClC)-3 expression and activity were analyzed. CFTR expression changed during the menstrual phases and was enhanced in endometriosis samples; its overexpression promoted endometrial cell proliferation, migration, and invasion throughout nuclear factor kappa-light-chain-enhancer of activated B cells-urokinase plasminogen activator receptor (NFκB-uPAR) signaling pathway. No connection between TRPs and the pathogenesis of endometriosis was found. AQP5 activity was estrogen-increased and, through phosphatidylinositol-3-kinase and protein kinase B (PI3K/AKT), helped in vivo implantation of ectopic endometrium. In vitro, AQP9 participated in extracellular signal-regulated kinases/p38 mitogen-activated protein kinase (ERK/p38 MAPK) pathway and helped migration and invasion stimulating matrix metalloproteinase (MMP)2 and MMP9. ClC-3 was also overexpressed in ectopic endometrium and upregulated MMP9. Conclusion: Available evidence suggests a pivotal role of CFTR, AQPs, and ClC-3 in endometriosis etiopathogenesis. However, data obtained are not sufficient to establish a direct role of ion channels in the etiology of the disease. Further studies are needed to clarify this relationship.