Progesterone receptor isoform B regulates the Oxtr - Plcl2 - Trpc3 pathway to suppress uterine contractility

Abstract

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.

Integrative genetic, genomic and transcriptomic analysis of heat shock protein and nuclear hormone receptor gene associations with spontaneous preterm birth

“…Variants rs11571145, rs1042838, and rs3740753 are missense variants (Pro22Leu, Val496Leu, and Ser180Thr, respectively, in the PGR-A isoform, and Pro186Leu, Val660Leu, and Ser344Thr, respectively, in the PGR-B isoform). The role of different PGR isoforms in pregnancy is well supported 44 , 45 . Especially, the expression of low affinity variant of PGR, PGR-A increases towards term labor 46 .…”

Progesterone Receptor Modulates Extraembryonic Mesoderm and Cardiac Progenitor Specification during Mouse Gastrulation

“…The balance of the PGR isoforms is important to promote the transition into partuition. PGR-A overexpression induces smooth muscle contractility of the uterus [ 62 ]. Similarly, during cardiac mesoderm specification, different PGR isoform activity could indicate a specific requirement in contractility of FHF and SHF cardiomyocytes.…”

“…Progesterone and its synthetic analogues are used as contraceptive agents [ 62 ] and a treatment for recurring early miscarriages [ 63 ]. Our work in mouse and cell models shows that PGR is essential not only for embryo implantation but also for embryonic development, thus further emphasizing its significance during pregnancy supporting embryonic life.…”

The role of epithelial progesterone receptor isoforms in embryo implantation

“…In the myometrium during pregnancy there is a shift in the ratio of these isoforms with a decrease in the ratio of PGRB to PGRA (Merlino et al, 2007). Expression of these isoforms in vitro in myometrial cells or in vivo in mice expressing these isoforms under the control of the Myh11 cre show distinct phenotypes and transcriptomes with PGRA being proinflammatory and regulating muscle contraction while PGRB is anti-inflammatory and promotes muscle relaxation (Mesiano et al, 2011;Peavey et al, 2021;Tan et al, 2012). Here, we show that expression of the PGR isoforms in the uterine epithelium are phenocopies with similar transcriptomes.…”