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Pregnancy |
Laboratoire de Physiologie et Physiopathologie,2 UMR-CNRS 7079, 75252 Paris CEDEX 05, France
Unité de Neuro-Gastroentérologie et Nutrition,3 INRA, 31931 Toulouse CEDEX 09, France
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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catecholamines, pregnancy, signal transduction, uterus
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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In many mammalian species, pregnancy is associated with a decrease of signaling pathways involved in uterine contraction. Indeed, activation of the Gq/PLC system by OT receptors (OTR), 
1-AR (adrenergic receptors), or muscarinic receptors (mR) was shown to be less effective during pregnancy [2–4]. This can be explained, at least in part, by the previously reported downregulation of receptors [3, 5] and Gq protein [6] at this period. Changes in the type and/or expression level of PLC isoforms could also contribute to this pregnancy-dependent decrease of PLC-linked signaling pathways. To date, 11 mammalian PLC isoforms have been isolated, including four ß, two 
, four 
, and a recently described 
isoform [7]. Among the different subfamilies of PLCs, PLCß members are triggered by G protein-coupled receptors. PLCß1, PLCß2, PLCß3, and PLCß4 are all stimulated by Ca2+, but are differently regulated by G protein subunits [7]. PLCß3 can be activated by both Gq/11 and Gß subunits, whereas PLCß1 and PLCß4 are more sensitive to Gq/11, and PLCß2 is strongly activated by the Gß complex [8]. Inhibition of the Gß-stimulated PLCß2 and PLCß3 was reported to occur through phosphorylation by the cAMP-dependent protein kinase (PKA) [9–11]. In rat myometrium, only some fragmentary data are available on the expression of PLCß isoforms and their regulation throughout pregnancy.
Pregnancy is also characterized by a potentiation of signaling pathways that maintain the uterus in a quiescent state. ß-AR are the most studied receptors that allow such an effect. These receptors stimulate adenylyl cyclase through the Gs protein, thereby enhancing myometrial intracellular concentrations of cAMP. The subsequent activation of PKA results in inhibition of myosin light chain kinase and activation of the plasma membrane and sarcoplasmic reticulum pumps that lower intracellular free Ca2+ [12]. Furthermore, ß-AR can also induce hyperpolarization of myometrial cells through activation of K+ channels. A number of tetraethylammonium (TEA)- and 4-aminopyridine (4-AP)-sensitive K+ channels have been described in myometrium, including Ca2+-activated, ATP-sensitive, and voltage-gated channels [13]. Activation of ß-AR was also shown to exert a negative regulation on the PLC pathway by reducing inositol phosphate (InsP) production of late pregnant myometrium through cAMP-dependent or -independent mechanisms [4, 14]. At midpregnancy, little is known about the cross-regulation between the myometrial ß-AR and the PLC system.
The present study was, therefore, undertaken to characterize and quantify by immunoblotting studies the myometrial PLCß isoforms expressed throughout pregnancy. We also studied the effect of isoproterenol on myometrial InsP production and uterine activity of midpregnant rat in basal conditions and in response to OT, phenylephrine (Phe), and carbachol (CCh) (1-adrenergic and muscarinic agonists, respectively). Contractile experiments were performed on both longitudinal and circular muscle layers. To determine the signaling pathway involved in the negative regulation exerted by ß-AR on the PLC system, we compared the effects of Forskolin and two K+ channel inhibitors, TEA and 4-AP. The obtained data contribute to the better understanding of the molecular mechanisms underlying uterine quiescence during pregnancy and the initiation of labor at term.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Krebs bicarbonate buffer was composed of the following: NaCl 117 mM, KCl 4.7 mM, MgSO4 1.1 mM, KH2PO4 1.2 mM, NaHCO3 24 mM, CaCl2 0.8 mM, glucose 1 mM, pH 7.4. Myo-[2-3H]inositol (10–25 Ci/mmol) and polyvinylidene difluoride membranes were purchased from Perkin Elmer Life Sciences (Paris, France). Rabbit polyclonal antibodies directed against the carboxyl termini of PLCß were obtained from Santa Cruz Biotechnology, Inc. (Santa Cruz, CA); horseradish peroxidase conjugated goat anti-rabbit antibody was from Jackson ImmunoResearch (West Grove, PA). TEA and 4-AP were kindly provided by Dr. P. Vincent, Paris, France. Isoproterenol, Forskolin, OT, Phe, and CCh were from Sigma (L'Isle d'Abeau, France); enhanced chemiluminescence reagent was from Amersham Pharmacia Biotech (Les Ulis, France); and AG1-X8 resin was from Bio-Rad Laboratories, Inc. (Marne la Coquette, France).
Animals and Tissues
Sprague Dawley rats were obtained from Janvier (Le Genest, France). The females were caged with males overnight and successful mating was determined by the presence of spermatozoa in the vaginal smear (Day 1 of pregnancy). Animals were killed by cervical dislocation at estrus (nonpregnant), Day 15 of pregnancy (midpregnancy), or during the expulsion of fetoplacental units (term) following the guidelines laid down by the National Institutes of Health (NIH) Guide. The uterine horns were quickly isolated and cut open lengthwise, and the fetoplacental units were removed. For plasma membrane and cytosolic preparations and InsP production studies, the myometrium was freed of adherent endometrium.
Preparation of Myometrial Plasma Membrane and Cytosolic Fractions
Myometrial tissue was homogenized in 0.5 mM EDTA and 10 mM Tris pH 7.4 supplemented with a cocktail of protease inhibitors (Sigma). After 10 min centrifugation at 4°C, supernatants were collected and submitted to 100 000 x g centrifugation at 4°C for 1 h to separate plasma membranes from cytosol. Pellet containing plasma membranes was resuspended in homogenization buffer, and protein concentration of plasma membrane and cytosolic fractions was determined according to Bradford [15], with bovine serum albumin as standard. Samples were stored at -80°C until use.
Immunoblotting
Twenty micrograms of myometrial plasma membrane and cytosolic fractions were subjected to SDS-Page in 7.5% gels and transferred to polyvinylidene difluoride membranes. The blots were blocked overnight at 4°C in Tris-buffered saline containing 5% nonfat dried milk and incubated for 1 h at room temperature with anti-PLCß (diluted 1:200). Incubation with secondary antibody (diluted 1:10 000) was carried out for 45 min at room temperature. Immunoreactive bands were visualized by the chemiluminescence detection system.
Myometrial InsP Production
Myometrial production of InsP was measured as briefly described. Myometrial strips (20 mg) were incubated at 37°C for 4 h with 7 µCi myo-[3H]inositol (0.4 µM) in 1 ml of Krebs bicarbonate buffer in the presence of 5% CO2/95% O2. Increasing concentrations of OT, Phe, or CCh were added after 10 min incubation of myometrial strips with 10 mM LiCl in Krebs bicarbonate buffer. Assays were stopped 15 min later by freezing the strips in liquid N2. When used, isoproterenol 100 nM or Forskolin 100 µM were added 15 min before the addition of OT, Phe, or CCh. Preincubation of strips with TEA (10 mM) and 4-AP (2 mM) was conducted for 5 min before adding isoproterenol. [3H]InsP were measured as previously described [16].
Isometric Contraction Measurements
Uterine strips of 4 mm long were prepared from pregnant rats and mounted in tissue baths containing 8 ml of Krebs bicarbonate buffer bubbled continuously with 5% CO2/95% O2 and warmed to 30°C. Depending on the orientation of the strips, we measured tissue tension of the circular inner or the longitudinal outer layer of uterine muscle using Bioscience UF1 tension transducer (Phymep, Paris, France). Strips were washed twice with Krebs buffer and allowed to equilibrate for 30 min under 0.7 g resting force. Response to cumulative doses of OT, Phe, or CCh (0.1 nM–1 mM) were examined either in the absence or presence of isoproterenol (100 nM) or Forskolin (100 µM). When tested, TEA (10 mM) plus 4-AP (2 mM) or KCl (30 mM) were added to the tissue bath for 5 min prior to the application of isoproterenol (100 nM). All drugs used represented 1:1000 of total volume. The concentration-response curves were recorded by computerized calculation of the integral under the tension/time curve for 3 min.
Statistical Studies
Results are expressed as means ± SEM. Statistical significance was assessed by Student t test for unpaired data. A P value less than 0.05 was considered to be significant.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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We performed immunoblotting studies on rat myometrial plasma membrane and cytosolic fractions using specific antibodies directed against PLCß1, PLCß2, PLCß3, and PLCß4. Rat brain, where the expression of the four PLCß isoforms has been previously reported, was used as positive control. As we have previously shown [16], PLCß1 (150 kDa), PLCß3 (150 kDa), and PLCß4 (130 kDa), but not PLCß2, are present in plasma membrane preparations (Fig. 1). PLCß1 and PLCß3 were detected in the cytosolic compartment as well, with a relatively high expression compared with plasma membranes. Interestingly, a specific band of 145 kDa corresponding to PLCß2 was also seen in the cytosol after a long time exposure, whereas no signal was detected for PLCß4 in this compartment.
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We then compared the expression of each myometrial PLCß isoform between nonpregnant, midpregnant, and term rats in both plasma membrane and cytosolic fractions. As illustrated in Figures 1 and 2A–C, the level of PLCß1, PLCß2, and PLCß3 declined at midpregnancy. Indeed, at this period PLCß1 and PLCß2 isoforms were hardly detectable, and the amount of PLCß3 decreased in both plasma membrane (-70%) and cytosolic (-50%) fractions. At term, the expression of these isoforms increased to reach a similar level to that observed in nonpregnant myometrium, at least for PLCß1 and PLCß3. Interestingly, PLCß4 presented a completely different pattern of expression (Figs. 1 and 2D). Indeed, this PLCß isoform was undetectable in nonpregnant myometrium. Its amount increased at midpregnancy and declined by 300% at term.
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These results show, for the first time, that rat myometrium differentially expresses PLCß isoforms during pregnancy.
Effect of Agonists on Myometrial InsP Production and Uterine Contraction in Midpregnant Rat
We compared the effect of OTR, 1-AR, or mR activation on PLC activity at midpregnancy. As illustrated in Figure 3A, OT, Phe, and CCh elicited a dose-dependent increase of myometrial InsP production. However, the efficacy and potency of responses were different between the three tested agonists. Indeed, the calculated EC50 values indicated the following rank order of efficacy: OT > Phe > CCh (3 nM, 47 nM, and 1.2 µM for OT, Phe, and CCh, respectively). In contrast, the maximal response was observed for CCh.
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Since myometrial PLC activation is linked to uterine contraction, we compared the responses of both longitudinally and circularly mounted strips to OT, Phe, and CCh. All uterine strips exhibited spontaneous rhythmic contractions a few minutes after being mounted in the bath (data not shown). The addition of increasing concentrations of agonists revealed a higher efficacy of OTR to increase uterine contraction compared with the other receptors, whatever the muscle layer studied (Fig. 3, B and C). However, OT was more efficient in the longitudinal muscle (EC50 values were of 3 and 100 nM in the longitudinal and circular muscles, respectively). Furthermore, while CCh similarly contracted both uterine muscle layers, a specific effect of Phe was observed only in the circular muscle (Fig. 3, B and C). In the longitudinal muscle, we noted a significant decrease of uterine contraction at high concentrations of Phe, probably due to its unspecific interaction with ß-AR as previously shown in mice [16].
Effect of ß-Adrenergic Activation on Myometrial InsP Production and Uterine Contraction in Midpregnant Rat
Pretreatment of myometrial strips with isoproterenol (100 nM, 15 min) decreased basal InsP production by 35% (Fig. 4A). Total InsP response to maximally effective OT (1 µM), Phe (1 µM), or CCh (10 µM) was also diminished to the same extent (Fig. 4A). However, the net response (InsP production above basal) was not affected by isoproterenol (+60%, +100%, and +160% for OT, Phe, and CCh in the absence or presence of isoproterenol). The EC50 values calculated for the three agonists were also unaltered by such pretreatment (data not shown).
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We also investigated whether activation of ß-AR alters uterine contraction. Pretreatment of uterine strips with isoproterenol significantly decreased spontaneous contractions in the longitudinal but not in the circular uterine muscle (Fig. 4, B and C). This is in agreement with the previously reported predominant localization of ß-AR in the longitudinal layer of myometrium [17]. Thus, all of the subsequent experiments were conducted in the longitudinal muscle. Pretreatment of uterine strips with isoproterenol did not block responses to OT or CCh, which were still able to increase contractile activity in a dose-dependent manner (Fig. 5, A and B). However, the obtained sigmoid dose-response curves for OT revealed a significant 30%–40% decrease in uterine tension in the presence of isoproterenol (Fig. 5C). The calculated EC50 values were not significantly altered by isoproterenol pretreatment (3.5 and 6 nM in the absence or presence of isoproterenol, respectively). Similar results were obtained for CCh (data not shown).
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Together these data indicate that activation of the ß-adrenergic pathway alters both InsP production and contractile activity of the longitudinal layer of myometrium at midpregnancy.
Mechanisms Involved in the ß-Adrenergic-Induced Decrease of Myometrial InsP Production and Uterine Contraction in Midpregnant Rat
It is well known that ß-AR increase cAMP production in pregnant rat myometrium. ß-AR have also been implicated in the activation of K+ channels in this tissue [13]. Therefore, we investigated which of these pathways mediates isoproterenol-induced effects at midpregnancy.
Forskolin (100 µM), a diterpene that acts downstream ß-AR by directly activating adenylyl cyclases, had no effect on basal InsP production (Fig. 6A). Interestingly, preincubation of myometrial strips with K+ channel inhibitors TEA (10 mM) plus 4-AP (2 mM) completely blocked the isoproterenol-induced decrease of InsP production (Fig. 6B).
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When incubated with uterine strips, TEA plus 4-AP evoked an immediate increase in uterine contraction, probably due to their ability to induce myometrial cell depolarization (Fig. 7A). Addition of isoproterenol suppressed this increase, but a remaining activity was still observed (Fig. 7A). Currently used to trigger myometrial membrane depolarization, KCl (30 mM) also elicited a rapid increase of uterine contraction (Fig. 7B). However, in this case no remaining activity was observed after isoproterenol application (Fig. 7B). This indicates that TEA and 4-AP partially blocked isoproterenol-induced relaxation at midpregnancy. Thus, a part of isoproterenol's effects involves the coupling of ß-AR receptors to K+ channels. When used, Forskolin was as potent as isoproterenol in inducing uterine relaxation (Fig. 7C).
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Altogether these data reveal that reduction of InsP production by ß-AR involves activation of K+ channels through a cAMP-independent mechanism. This could contribute to the induction of relaxation of the longitudinal layer of myometrium at midpregnancy.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Using specific antibodies, we showed the presence of the four members of the PLCß family (PLCß1, PLCß2, PLCß3, and PLCß4) in rat myometrium. PLCß1 and PLCß3 are present in both plasma membrane and cytosolic fractions, whereas PLCß2 was detectable in the cytosol after a long time exposure. The latter finding can explain why many studies on plasma membrane preparations, including ours, failed to detect the PLCß2 isoform in nonpregnant and pregnant myometrium [16, 18]. Expression of PLCß4 (130 kDa) was observed only in myometrial plasma membranes, indicating that this isoform corresponds to PLCß4a, the splice that can be activated by the Gq protein [19].
Our quantitative analysis revealed for the first time that rat myometrium differentially expresses PLCß isoforms during the course of pregnancy. At midpregnancy, when the uterus is under progesterone dominance, the amounts of PLCß1, PLCß2, and PLCß3 are decreased, whereas that of PLCß4 is increased. At the opposite, when the myometrium is under estrogen dominance (estrus and term), the expression of PLCß1, PLCß2, and PLCß3 is upregulated, whereas that of PLCß4 is downregulated. Therefore, it is tempting to suggest that progesterone and/or estradiol directly or indirectly regulate the expression of myometrial PLCß isoforms.
Downregulation of PLCß1, PLCß2, and PLCß3, together with that of Gq [6], can explain, at least in part, the low ability of many G protein-coupled receptors to induce phosphoinositide hydrolysis and uterine contraction during pregnancy [2–4]. The physiological meaning of PLCß4 upregulation at this period remains to be determined. A possible explanation is that PLCß4 is less efficient than the other members of the PLCß family to hydrolyze phosphatidylinositol 4,5-bisphosphate and induce contraction. Alternatively, PLCß4 could be involved in other myometrial responses such as cell growth and/or hypertrophy during pregnancy. In neonatal rat cardiomyocytes, PLCß expression seems to be required for the induction of early genes by hypertrophic factors like growth hormone and insulin-like growth factor I [20].
Regulation of Myometrial InsP Production and Uterine Contraction by Agonists in Midpregnant Rat
We report in the present work that OTR, 1-AR, and mR are linked to myometrial PLC activation and uterine contraction in midpregnant rat. Responses differ, however, depending on the type of activated receptor. Indeed, we noted a higher efficacy of OTR compared with 1-AR and mR to stimulate InsP production and induce contraction, whatever the uterine muscle layer studied. Whether or not these receptors are differently coupled to myometrial Gq protein and PLCß4 should be further examined in future studies. Uterine responses to agonists are also dependent on the type of muscle layer. Indeed, whereas both layers responded similarly to CCh, longitudinal muscle was more sensitive to OT. In addition, a specific effect of 1-AR was found in the circular muscle only. This probably reflects a layer-dependent distribution of OTR and 1-AR. We have previously shown that 1-AR are predominantly localized in the rat circular muscle [17], and a recent work reported that OTR density is five-fold more important in the longitudinal muscle layer of swine uterus [21].
Regulation of PLC System and Uterine Contraction by ß-AR in Midpregnant Rat
Previous studies reported that activation of myometrial ß-AR significantly reduced OT- and CCh-stimulated InsP production in late pregnant rat [4, 14]. No data were available at midpregnancy, a different situation in terms of hormonal environment and expression of signaling transduction entities. Furthermore, none of these groups compared the effects of isoproterenol on both InsP production and uterine contraction. The present work shows that activation of ß-AR decreases both basal and OT- and CCh-stimulated InsP production and uterine contraction in midpregnant rat. Interestingly, neither the net response nor the EC50 values for OTR and mR were affected. This indicates that isoproterenol pretreatment does not alter the ability of receptors to activate PLC.
In the present report, we also show evidence that ß-AR exert their inhibitory effects on the PLC signaling pathway through a cAMP-independent pathway. Indeed, Forskolin, at a concentration that increases maximally myometrial adenylyl cyclase activity at midpregnancy [22], failed to cause any attenuation of InsP production. Interestingly, two global K+ channel inhibitors, TEA and 4-AP, prevented the effect of isoproterenol. Our interpretation of these data is that hyperpolarization induced by activation of K+ channels indirectly affects InsP production by reducing the intracellular concentrations of Ca2+. First, PLC enzymes are highly sensitive to Ca2+ [7]. Second, activation of K+ channels by ß-AR results in the closure of voltage-gated Ca2+ channels in pregnant rat myometrium [14]. Therefore, a ß-adrenergic-induced decrease of InsP production is probably due to the suppression of the Ca2+-stimulated component of PLC enzymes in midpregnant myometrium. Among the different TEA- and 4-AP-sensitive currents that have been described in pregnant myometrium, Ca2+-activated and ATP-sensitive K+ channels were reported to mediate ß-adrenergic-induced hyperpolarization of myometrial cells [23, 24]. Activation of these channels seems to occur not only through cAMP-dependent phosphorylation [24], but also directly via a G protein [24, 25]. Further studies should be addressed to determine the precise mechanism underlying ß-adrenergic activation of K+ channels in midpregnant rat myometrium. This regulation may have a supportive role in the cAMP-dependent actions of ß-AR at midpregnancy. Indeed, our contraction experiments showed that TEA and 4-AP only partially blocked ß-adrenergic-mediated effects, whereas Forskolin was as potent as isoproterenol in inducing uterine relaxation.
Our data contrast with those obtained at late pregnancy, where attenuation of rat myometrial OT-stimulated InsP production by isoproterenol was found to involve inhibition of PLCß3 by a cAMP/PKA pathway [4]. In support of the present work, the potential PKA targets PLCß2 and PLCß3 [9–11] are downregulated at midpregnancy (immunoblotting studies). Our interpretation of such a discrepancy is that, depending on the type of PLCß expressed during pregnancy, ß-AR use different mechanisms to counteract the InsP increase. Thus, ß-AR may operate through suppression of Ca2+-dependent stimulation of PLCß4 at midpregnancy, and both suppress Ca2+-dependent stimulation of PLCß1 and inhibit PLCß2 and PLCß3 via phosphorylation by PKA at late pregnancy. At this time, these complementary mechanisms would help to inhibit myometrial activity during uterine preparation for parturition. Indeed, up-regulation of many contraction-associated proteins occurs while the uterus is still quiescent. For instance, the expression of PLCß1, PLCß2, and PLCß3 is maximal from Day 19 of pregnancy (data not shown).
In summary, we show that the amount of myometrial PLCß1, PLCß2, and PLCß3 declines at midpregnancy. This, together with the downregulation of Gq protein, can explain, at least in part, the decreased responsiveness of myometrium to activation of PLC-linked signaling pathways at this period. Concomitant stimulation of ß-AR exerts a negative regulation on PLC activity through activation of K+ channels in the longitudinal layer of myometrium. Altogether, these mechanisms could act to reduce responses to contractant hormones and neurotransmitters during pregnancy in order to permit development of fetoplacental units. At term, upregulation of signaling transduction entities of the PLC pathway (Gq, PLCß1, PLCß2, and PLCß3) together with the desensitization of ß-AR could help to initiate uterine contraction. The increased expression of PLCß4 at midpregnancy is intriguing. Future studies should evaluate whether this isozyme is involved in other responses such as myometrial cell growth and/or hypertrophy.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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Received: 24 July 2003.
First decision: 20 August 2003.
Accepted: 21 October 2003.
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REFERENCES |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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