Ablation of connexin43 in uterine smooth muscle cells of the mouse causes delayed parturition

Döring, Britta; Shynlova, Oksana; Tsui, Prudence; Eckardt, Dominik; Janssen‐Bienhold, Ulrike; Hofmann, Franz; Feil, Susanne; Feil, Robert; Lye, Stephen J.; Willecke, Klaus

doi:10.1242/jcs.02892

Cited by 99 publications

(76 citation statements)

References 45 publications

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“…Treatment of myometrial tissue with iloprost for 48 h resulted in a significant increase in connexin 43 expression compared with control ( Figure 3). Based on previous studies showing the importance of connexin 43 in regulating parturition (11), these data suggest that iloprost may also enhance oxytocin-induced contractility by increasing connexin 43 expression.…”

Section: Figuresupporting

confidence: 52%

“…Notably, mice with smooth muscle-specific deletion of connexin 43 had a significantly prolonged birth process, which suggests that connexin 43 is necessary for the initiation and progression of labor (11). Also important for myometrial activation are the proteins that make up the contractile apparatus, including the thick filament-associated protein smooth muscle myosin heavy chain (SM-MHC) and the thin filament-associated proteins α-SMA, calponin, and h-caldesmon (7,12).…”

Section: Introductionmentioning

confidence: 99%

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Prostacyclin primes pregnant human myometrium for an enhanced contractile response in parturition

Fetalvero¹,

Zhang²,

Shyu³

et al. 2008

J. Clin. Invest.

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An incomplete understanding of the molecular events that regulate the myometrial transition from the quiescent pregnant state to the active contractile state during labor has hindered the development of improved therapies for preterm labor. During myometrial activation, proteins that prime the smooth muscle for contraction are upregulated, allowing maximal responsiveness to contractile agonists and thereby producing strong phasic contractions. Upregulation of one such protein, COX-2, generates PGs that induce contractions. Intriguingly, the predominant myometrial PG produced just prior to labor is prostacyclin (PGI 2 ), a smooth muscle relaxant. However, here we have shown that activation of PGI 2 receptor (IP) upregulated the expression of several contractile proteins and the gap junction protein connexin 43 through cAMP/PKA signaling in human myometrial tissue in organ and cell culture. Functionally, these IP-dependent changes in gene expression promoted an enhanced contractile response to oxytocin in pregnant human myometrial tissue strips, which was inhibited by the IP antagonist RO3244794. Furthermore, contractile protein induction was dependent on the concentration and time of exposure to the PGI 2 analog iloprost and was blocked by both RO3244794 and PKA knockdown. We therefore propose that PGI 2 -mediated upregulation of contractile proteins and connexin 43 is a critical step in myometrial activation, allowing for a maximal contractile response. Our observations have important implications regarding activation of the myometrium prior to the onset of labor.

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Section: Figuresupporting

confidence: 52%

Section: Introductionmentioning

confidence: 99%

Prostacyclin primes pregnant human myometrium for an enhanced contractile response in parturition

Fetalvero¹,

Zhang²,

Shyu³

et al. 2008

J. Clin. Invest.

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“…CXN-43 is a protein responsible for the formation of gap junctions in the myometrium, which mediate intercellular coupling to coordinate the synchronous myometrial contractions necessary for successful labor. In addition, mice with a smooth muscle-specific deletion of the CXN-43 gene manifest a significant delay in the timing of parturition (28). The action of oxytocin as an uterotonic agent is widely accepted.…”

Section: Discussionmentioning

confidence: 99%

miR-200 family and targets, ZEB1 and ZEB2, modulate uterine quiescence and contractility during pregnancy and labor

Renthal

Chen²,

Williams

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

258

239

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Throughout most of pregnancy, uterine quiescence is maintained by increased progesterone receptor (PR) transcriptional activity, whereas spontaneous labor is initiated/facilitated by a concerted series of biochemical events that activate inflammatory pathways and have a negative impact on PR function. In this study, we uncovered a previously undescribed regulatory pathway whereby micro-RNAs (miRNAs) serve as hormonally modulated and conserved mediators of contraction-associated genes in the pregnant uterus in the mouse and human. Using miRNA and gene expression microarray analyses of uterine tissues, we identified a conserved family of miRNAs, the miR-200 family, that is highly induced at term in both mice and humans as well as two coordinately downregulated targets, zinc finger E-box binding homeobox proteins ZEB1 and ZEB2, which act as transcriptional repressors. We also observed up-regulation of the miR-200 family and down-regulation of ZEB1 and ZEB2 in two different mouse models of preterm labor. We further demonstrated that ZEB1 is directly up-regulated by the action of progesterone (P 4 )/PR at the ZEB1 promoter. Excitingly, we observed that ZEB1 and ZEB2 inhibit expression of the contractionassociated genes, oxytocin receptor and connexin-43, and block oxytocin-induced contractility in human myometrial cells. Together, these findings implicate the miR-200 family and their targets, ZEB1 and ZEB2, as unique P 4 /PR-mediated regulators of uterine quiescence and contractility during pregnancy and labor and shed light on the molecular mechanisms involved in preterm birth.A lthough premature labor is the leading cause of neonatal morbidity and mortality in developed countries, the signaling mechanisms that maintain uterine quiescence during pregnancy and promote increased uterine contractility leading to labor at term and preterm remain incompletely defined (1). In mammalian pregnancy, uterine quiescence is maintained by elevated circulating progesterone (P 4 ) acting via the progesterone receptor (PR). Conversely, parturition is associated with a decline in maternal circulating P 4 and/or a decrease in the function of the PR, termed "functional P 4 withdrawal," (2, 3) and an increased inflammatory response within the uterus and cervix (4). Studies from a number of laboratories, including our own, suggest that P 4 and PR maintain uterine quiescence until term by inhibiting expression of contraction-associated genes [e.g., connexin-43 (CXN-43), oxytocin receptor (OXTR), cyclooxygenase 2 (COX-2)] in the myometrium, in part, via anti-inflammatory actions. For example, P 4 and PR inhibit activation of COX-2 expression in myometrial cells through direct interaction of PR with NF-κB p65 (5) and by P 4 -induced expression of the NF-κB inhibitor, IκB-α (6).Recently, it has been shown that micro-RNAs (miRNAs) play especially powerful roles in vascular smooth muscle cells and in female reproduction, wherein they have been implicated in proliferation, differentiation, and hormone responsiveness (7-9). The identification o...

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“…As a consequence, GJA1 is up-regulated following the onset of labour and during delivery (Garfield et al 1977, 1995, Chow & Lye 1994, Orsino et al 1996. GJA1 plays a key role in parturition as its myometrial loss leads to defects in physiological coordination of uterine contractions, and labour is subsequently prolonged (Cluff et al 2006, Doring et al 2006. PTGS2 is responsible for the synthesis of the prostaglandins, PGF 2a and PGE 2 , which regulate uterine activity during pregnancy and parturition (Zuo et al 1994).…”

Section: Introductionmentioning

confidence: 99%

The effects of a high-fat, high-cholesterol diet on markers of uterine contractility during parturition in the rat

Elmes

Tan²,

Cheng³

et al. 2011

Reproduction

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Increasing levels of obesity within women of reproductive age is a major concern in the UK. Approximately, 13% of women aged !30 and 22% of 31-to 40-year-old women are obese. Obesity increases complications during pregnancy and the risk of caesarean section due to prolonged labour and poor uterine activity. The aim was to investigate whether a high-fat, high-cholesterol (HFHC) diet decreases markers of uterine contractility during parturition in the rat. Female Wistar rats were fed control (CON, nZ10) or HFHC (nZ10) diets for 6 weeks. Animals were mated and, once pregnant, maintained on their diet throughout gestation. On gestational day 19, rats were monitored continuously and killed at the onset of parturition. Body and fat depot weights were recorded. Myometrial tissue was analysed for cholesterol (CHOL), triglycerides (TAG), and expression of the contractile associated proteins gap junction protein alpha 1 (GJA1; also known as connexin-43, CX-43), prostaglandin-endoperoxide synthase 2 (PTGS2; also known as cyclo-oxygenase-2, COX-2) and caveolin-1 (CAV1) and maternal plasma for prostaglandin F 2a (PGF 2a ) and progesterone. HFHC fed rats gained greater weight than CON (P!0.003) with significant increases in peri-renal fat (P!0.01). The HFHC diet increased plasma CHOL, TAG and progesterone, but decreased PGF 2a versus CON (P!0.01, P!0.01, PZ0.05 and P!0.02 respectively). Total CHOL and TAG levels of uterine tissue were similar. However, HFHC fed rats showed significant increases in PTGS2 (P!0.037), but decreases in GJA1 and CAV1 (PZ0.059). In conclusion, a HFHC diet significantly increases body weight and alters lipid profiles that correlate with decreases in key markers of uterine contractility. Further work is required to ascertain whether these changes have adverse effects on uterine activity.

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Ablation of connexin43 in uterine smooth muscle cells of the mouse causes delayed parturition

Cited by 99 publications

References 45 publications

Prostacyclin primes pregnant human myometrium for an enhanced contractile response in parturition

Prostacyclin primes pregnant human myometrium for an enhanced contractile response in parturition

miR-200 family and targets, ZEB1 and ZEB2, modulate uterine quiescence and contractility during pregnancy and labor

The effects of a high-fat, high-cholesterol diet on markers of uterine contractility during parturition in the rat

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