Myometrial Progesterone Receptor Isoform B Regulates the Phospholipase C Pathway and Suppresses Uterine Contractility

ABSTRACT: Uterine contractile dysfunction leads to pregnancy complications such as preterm birth and labor dystocia. Progesterone is necessary to suppress uterine contractions to prevent premature labor. As humans maintain high levels of progesterone throughout parturition, a functional progesterone withdrawal hypothesis suggests that relative levels of myometrial progesterone receptor isoforms PGR-A and PGR-B switch at parturition, where PGR-B promotes a relaxed state and PGR-A result in increased uterine contractility. Our objective is to determine the effects of altered levels of PGR-B and PGR-A in the mouse myometrium on pregnancy and parturition using transgenic mouse models in which the relative levels of these isoforms are altered specifically in the myometrium. Overexpression of PGR-B is associated with a markedly increased gestational length compared to control mice. In both ex vivo and in vivo experiments, myometrium of PGR-B overexpressing mice have prolonged labor, a significant decrease in uterine contractility, and a high incidence of labor dystocia. Conversely, overexpression of PGR-A is associated with an increase in uterine contractility without a change in gestational length. Uterine RNAseq at mid-pregnancy identified isoform-specific downstream targets and genes that were commonly regulated by both PGR isoforms. Gene signature analyses further revealed that PGR-B promotes muscle relaxation and that PGR-A is pro-inflammation. High levels of PGR-B manifest a genetic profile of a blunted phospholipase C pathway that mediates oxytocin and angiotensin II induced muscle contraction. These findings provided in vivo support that PGR isoform levels determine distinct transcriptomic landscapes and pathways in myometrial function and labor.

ORGANISM(S): Mus musculus

PROVIDER: GSE146634 | GEO | 2021/02/24

REPOSITORIES: GEO