Molecular pathways regulating contractility in rat uterus through late gestation and parturition

Taggart, Michael J.; Arthur, Patrice; Zavan, Barbara; Mitchell, Bryan F.

doi:10.1016/j.ajog.2012.04.036

Cited by 16 publications

(18 citation statements)

References 41 publications

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“…In support of this finding, in primary cultured human pregnant myometrial cells, ROCK1 and ROCK2 knockdown by siRNA significantly reduced basal MYPT1 Thr 853 phosphorylation but only caused a nonsignificant trend of decreased Thr 696 phosphorylation (90). In rats, ROCK1/2 mRNA was increased at full term or during labor (167,230,231); in mice, ROCK1/2 protein was increased during gestation (201). In humans, increased myometrial ROCK1/2 during pregnancy was reported (146); however, subsequent studies showed that myometrial ROCK1/2 mRNA and protein remained unchanged during human pregnancy and labor (65,120,123,200).…”

Section: Role Of Pp1 In Smooth Muscle Contractilitysupporting

confidence: 59%

Role of serine-threonine phosphoprotein phosphatases in smooth muscle contractility

Butler

Paul

Europe-Finner

et al. 2013

American Journal of Physiology-Cell Physiology

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The degree of phosphorylation of myosin light chain 20 (MLC20) is a major determinant of force generation in smooth muscle. Myosin phosphatases (MPs) contain protein phosphatase (PP) 1 as catalytic subunits and are the major enzymes that dephosphorylate MLC20. MP regulatory targeting subunit 1 (MYPT1), the main regulatory subunit of MP in all smooth muscles, is a key convergence point of contractile and relaxatory pathways. Combinations of regulatory mechanisms, including isoform splicing, multiple phosphorylation sites, and scaffolding proteins, modulate MYPT1 activity with tissue and agonist specificities to affect contraction and relaxation. Other members of the PP1 family that do not target myosin, as well as PP2A and PP2B, dephosphorylate a range of proteins that affect smooth muscle contraction. This review discusses the role of phosphatases in smooth muscle contractility with a focus on MYPT1 in uterine smooth muscle. Myometrium shares characteristics of vascular and other visceral smooth muscles yet, during healthy pregnancy, undergoes hypertrophy, hyperplasia, quiescence, and labor as physiological processes. Myometrium presents an accessible model for the study of normal and pathological smooth muscle function, and a better understanding of myometrial physiology may allow the development of novel therapeutics for the many disorders of myometrial physiology from preterm labor to dysmenorrhea.

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Section: Role Of Pp1 In Smooth Muscle Contractilitysupporting

confidence: 59%

Role of serine-threonine phosphoprotein phosphatases in smooth muscle contractility

Butler

Paul

Europe-Finner

et al. 2013

American Journal of Physiology-Cell Physiology

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“…In this study we examined changes in PR isoform expression via determining mRNA levels, an approach which is consistent with other studies in the field [40]. Nevertheless, we are aware that PR isoform protein levels may reflect PR function more closely than mRNA abundance especially in pregnancies complicated by intrauterine inflammation [41].…”

Section: Discussionmentioning

confidence: 97%

Modulation of Progesterone Receptor Isoform Expression in Pregnant Human Myometrium

Ilicic

Zakár

Paul

2017

BioMed Research International

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Background. Regulation of myometrial progesterone receptor (PR) expression is an unresolved issue central to understanding the mechanism of functional progesterone withdrawal and initiation of labor in women. Objectives. To determine whether pregnant human myometrium undergoes culture-induced changes in PR isoform expression ex situ and, further, to determine if conditions approaching the in vivo environment stabilise PR isoform expression in culture. Methods. Term nonlaboring human myometrial tissues were cultured under specific conditions: serum supplementation, steroids, stretch, cAMP, PMA, PGF2α, NF-κB inhibitors, or TSA. Following 48 h culture, PR-T, PR-A, and PR-B mRNA levels were determined using qRT-PCR. PR-A/PR-B ratios were calculated. Results. PR-T and PR-A expression and the PR-A/PR-B ratio significantly increased in culture. Steroids prevented the culture-induced increase in PR-T and PR-A expression. Stretch blocked the effects of steroids on PR-T and PR-A expression. PMA further increased the PR-A/PR-B ratio, while TSA blocked culture-induced increases of PR-A expression and the PR-A/PR-B ratio. Conclusion. Human myometrial tissue in culture undergoes changes in PR gene expression consistent with transition toward a laboring phenotype. TSA maintained the nonlaboring PR isoform expression pattern. This suggests that preserving histone and/or nonhistone protein acetylation is critical for maintaining the progesterone dependent quiescent phenotype of human myometrium in culture.

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“…This study examined whether non-laboring myometrial tissues and strips undergo changes in culture that are consistent with transition to a pro-contractile, laboring phenotype. We determined gene expression changes as quantitative assessment of mRNA in preference to semi-quantitative estimates of protein levels by Western blot (30). Notably, recent studies examining protein profiles in mammalian cells have found that transcription, not translation, chiefly determines protein abundance (31), and that during periods of dynamic change, such as that occurring during phenotype transition, changes in mRNA abundance play a particularly dominant role in controlling changes in protein levels (32).…”

Section: Discussionmentioning

confidence: 99%

The expression of genes involved in myometrial contractility changes during <i>ex situ</i> culture of pregnant human uterine smooth muscle tissue

Ilicic

Butler

Zakár

et al. 2017

J. Smooth Muscle Res.

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Background: Ex situ analyses of human myometrial tissue has been used to investigate the regulation of uterine quiescence and transition to a contractile phenotype. Following concerns about the validity of cultured primary cells, we examined whether myometrial tissue undergoes culture-induced changes ex situ that may affect the validity of in vitro models. Objectives: To determine whether human myometrial tissue undergoes culture-induced changes ex situ in Estrogen receptor 1 (ESR1), Prostaglandin-endoperoxide synthase 2 (PTGS2) and Oxytocin receptor (OXTR) expression. Additionally, to determine whether culture conditions approaching the in vivo environment influence the expression of these key genes. Methods: Term non-laboring human myometrial tissues were cultured in the presence of specific treatments, including; serum supplementation, progesterone and estrogen, cAMP, PMA, stretch or NF-κB inhibitors. ESR1, PTGS2 and OXTR mRNA abundance after 48 h culture was determined using quantitative RT-PCR. Results: Myometrial tissue in culture exhibited culture-induced up-regulation of ESR1 and PTGS2 and down-regulation of OXTR mRNA expression. Progesterone prevented culture-induced increase in ESR1 expression. Estrogen further up-regulated PTGS2 expression. Stretch had no direct effect, but blocked the effects of progesterone and estrogen on ESR1 and PTGS2 expression. cAMP had no effect whereas PMA further up-regulated PTGS2 expression and prevented decline of OXTR expression. Conclusion: Human myometrial tissue in culture undergoes culture-induced gene expression changes consistent with transition toward a laboring phenotype. Changes in ESR1, PTGS2 and OXTR expression could not be controlled simultaneously. Until optimal culture conditions are determined, results of in vitro experiments with myometrial tissues should be interpreted with caution.

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Molecular pathways regulating contractility in rat uterus through late gestation and parturition

Cited by 16 publications

References 41 publications

Role of serine-threonine phosphoprotein phosphatases in smooth muscle contractility

Role of serine-threonine phosphoprotein phosphatases in smooth muscle contractility

Modulation of Progesterone Receptor Isoform Expression in Pregnant Human Myometrium

The expression of genes involved in myometrial contractility changes during <i>ex situ</i> culture of pregnant human uterine smooth muscle tissue

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