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13 October 2020 Progesterone receptor membrane components: key regulators of fetal membrane integrity
Violetta Lozovyy, Lauren Richardson, George Saade, Ramkumar Menon
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Abstract

Pro-pregnancy hormone progesterone (P4) helps to maintain a quiescent status of uterine tissues during gestation. However, P4's functional role in maintaining fetal membrane (amniochorion) integrity remains unclear. P4 functions through its membrane receptors (progesterone receptor membrane components (PGRMCs)) as fetal membrane cells lack nuclear receptors. This study screened the differential expression of PGRMCs in the fetal membranes and tested P4–PGRMC interactions under normal and oxidative stress (OS) conditions expected that can disrupt P4–PGRMC interactions impacting fetal membrane stability resulting in parturition. Human fetal membranes were collected from term and preterm deliveries (N = 5). Immunohistochemistry and western blot localized and determined differential expression of P4 receptors. Primary amnion epithelial, mesenchymal (AMCs), and chorion cell were treated with P4 alone or co-treated (P4 + OS induced by cigarette smoke extract (CSE)). Proximity ligation assay (PLA) documented P4–receptor binding, whereas P4 enzyme-linked immunosorbent assay documented culture supernatant levels. Immunohistology confirmed lack of nuclear progesterone receptors; however, confirmed expressions of PGRMC 1 and 2. Term labor (P = 0.01) and preterm rupture (P = 0.01) are associated with significant downregulation of PGRMC2. OS-induced differential downregulation of PGRMCs in both amnion and chorion cells (all P < 0.05) and downregulates P4 release (AMCs; P = 0.01). The PLA showed preferential receptor–ligand binding in amnion and chorion cells. Co-treatment of P4 + CSE did not reverse CSE-induced effects. In conclusion, P4–PGRMCs interaction maintains fetal membranes' functional integrity throughout pregnancy. Increased OS reduces endogenous P4 production and cell type-dependent downregulation of PGRMCs. These changes can lead to fetal membrane-specific “functional progesterone withdrawal,” contributing to the dysfunctional fetal membrane status seen at term and preterm conditions.

Summary sentence

Oxidative stress-induces cells type-dependent changes in progesterone receptor membrane component 1 and 2 expression, which could contribute to the disruption of human fetal membranes both at term and preterm labor.

© The Author(s) 2020. Published by Oxford University Press on behalf of Society for the Study of Reproduction. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com
Violetta Lozovyy, Lauren Richardson, George Saade, and Ramkumar Menon "Progesterone receptor membrane components: key regulators of fetal membrane integrity," Biology of Reproduction 104(2), 445-456, (13 October 2020). https://doi.org/10.1093/biolre/ioaa192
Received: 30 June 2020; Accepted: 9 October 2020; Published: 13 October 2020
KEYWORDS
amnion membrane
functional progesterone withdrawal
PGRMC1
PGRMC2
PPROM
preterm birth
progesterone
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