Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 118, Issue 11, Pages -Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.2011643118
Keywords
myometrium; progesterone receptor isoform; contractility; labor; parturition
Categories
Funding
- Intramural Research Program of the NIEHS, NIH [Z1AES103311, Z99ES999999]
- NIH extramural research program of the National Institute of Child Health and Human Development [RO1 HD042311]
- NIEHS Postbaccalaureate Intramural Research Training Award
- Burroughs Wellcome Fund
- March of Dimes
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The study revealed that overexpression of progesterone receptor PGR-B leads to relaxation of uterine muscles, prolonged gestational length, and increased incidence of labor dystocia, while overexpression of PGR-A increases uterine muscle contraction without affecting gestational length.
Uterine contractile dysfunction leads to pregnancy complications such as preterm birth and labor dystocia. In humans, it is hypothesized that progesterone receptor isoform PGR-B promotes a relaxed state of the myometrium, and PGR-A facilitates uterine contraction. This hypothesis was tested in vivo using transgenic mouse models that overexpress PGR-A or PGR-B in smooth muscle cells. Elevated PGR-B abundance results in a marked increase in gestational length compared to control mice (21.1 versus 19.1 d respectively, P < 0.05). In both ex vivo and in vivo experiments, PGR-B overexpression leads to prolonged labor, a significant decrease in uterine contractility, and a high incidence of labor dystocia. Conversely, PGR-A overexpression leads to an increase in uterine contractility without a change in gestational length. Uterine RNA sequencing at midpregnancy identified 1,174 isoform-specific downstream targets and 424 genes that are commonly regulated by both PGR isoforms. Gene signature analyses further reveal PGR-B for muscle relaxation and PGR-A being proinflammatory. Elevated PGR-B abundance reduces Oxtr and Trpc3 and increases Plcl2 expression, which manifests a genetic profile of compromised oxytocin signaling. Functionally, both endogenous PLCL2 and its paralog PLCL1 can attenuate uterine muscle cell contraction in a CRISPRa-based assay system. These findings provide in vivo support that PGR isoform levels determine distinct transcriptomic landscapes and pathways in myometrial function and labor, which may help further the understanding of abnormal uterine function in the clinical setting.
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