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Program in Development and Fetal Health, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, and the Departments of Obstetrics and Gynecology and Physiology, University of Toronto, Toronto, Ontario, Canada
Address all correspondence and requests for reprints to: Dr. Stephen J. Lye, Program in Development and Fetal Health, Samuel Lunenfeld Research Institute at Mount Sinai, 600 University Avenue, Suite 775, Toronto, Ontario, Canada M5G 1X5. E-mail: Stephen_Lye{at}compuserve.com
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Introduction |
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Gap junctions are recognized as playing a major role in the regulation and coordination of myometrial contractile activity. Gap junctions are structurally differentiated areas of the plasma membrane that contain collections of transmembrane channels linking the cytoplasmic compartments of adjacent cells (3, 4). These channels provide cells with a means of intercellular communication and represent sites for the direct cell to cell transfer of ions and small molecules without exposure to the extracellular space. Gap junctions also provide sites of low electrical resistance, and in the myometrium they are thought to function in the initiation of labor by allowing the propagation of electrical impulses throughout the myometrium, thus facilitating the synchronous muscle contractility of labor. Structurally, gap junctions are composed of a hexameric assembly of integral membrane proteins (connexins) arranged symmetrically around a central aqueous pore (3). Within the pregnant myometrium two connexin proteins are particularly abundant, but exhibit temporally distinct patterns of expression. The expression of connexin-43 (Cx-43) is low throughout most of pregnancy, but increases dramatically immediately before the onset of labor (5). In contrast, the expression of Cx-26 is highest during late pregnancy, but falls to low levels during labor (6). Although Cx-43 is generally thought to mediate the increased electrical coupling within the myometrium during labor, the contribution of Cx-26 to the regulation of myometrial contractility remains to be determined.
Pregnancies with more than one fetus have higher rates of premature delivery and perinatal mortality than singleton pregnancies (7). Thus, although only 2.6% of all neonates were twins, they accounted for 12.2% of all preterm infants, 15.4% of all neonatal deaths, and 9.5% of all fetal deaths. This poor outcome of twins is largely attributable to their increased incidence of preterm birth. The mechanisms that predispose multifetal pregnancies to preterm birth are not known; however, it is possible that the increased intrauterine volume imposes an increase in tension within the uterine wall and, hence, a stretch or distension of the uterine myocytes. It has been widely recognized that mechanical strain or stretch is a major regulator of smooth muscle contractility. Stretch has been shown to induce depolarization of the cell membrane, increased action potential frequency, and subsequent contraction in smooth muscle isolated from the gastrointestinal tract (8), respiratory tract (9), and blood vessels (10, 11). Although fewer data are available about the effects of stretch in regulating myometrial contractility, similar processes are believed to occur. For example, Manabe et al. (12) reported that distension of the human uterus by inflation of an intrauterine balloon with physiological saline induced labor within 5 h.
Although the effects of stretch could be mediated by premature activation of the myometrium, little is known about whether stretch can induce the expression of candidate CAPs in the myometrium. However, Wathes and Porter (13) reported an increase in the number of gap junctions after in vivo distension of the nonpregnant rat uterus by an intrauterine balloon. The purpose of this study was to test the hypotheses that stretch is an important modulator of myometrial activation and operates by increasing the expression of CAPs in this smooth muscle. In light of the data of Wathes and Porter (13) described above and of our own demonstration of the expression of two major myometrial gap junction proteins during pregnancy (5, 6), we have investigated whether stretch might increase the expression of Cx-43 and Cx-26 in nonpregnant and pregnant myometria. We initially determined whether mechanical stretch of the uterus could increase the expression of these connexins in the myometrium of nonpregnant ovariectomized rats. Although uterine stretch as a result of the increasing intrauterine volume during pregnancy may be an important regulator of connexin expression and, hence, myometrial activation, most pregnancies, including lower order, multifetal pregnancies, do not result in preterm labor. It would appear, therefore, that mechanisms may have evolved to attenuate the effects of stretch during pregnancy. We, therefore, investigated whether progesterone (a key hormone responsible for the maintenance of pregnancy) and pregnancy itself could block stretch-induced connexin expression. Finally, we examined whether during labor, when progesterone levels are falling, the effects of stretch would be reestablished.
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Materials and Methods |
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Nonpregnant studies
Mature virgin female rats (
250 g) received daily sc
injections of 17ß-estradiol (5 µg in 0.2 ml vehicle containing 90%
corn oil and 10% ethanol) for 3 days and 17ß-estradiol (5 µg) plus
progesterone (5 mg in 0.2 ml vehicle) for 2 days to synchronize the
hormonal environment and to prepare the uterus for subsequent catheter
placement. On the following day, animals were randomized into three
groups.
Group 1 (n = 9). Under general anesthesia with ip
injection of a mixture of ketamine (70 mg/kg) and xylazine (7 mg/kg),
the rats were bilaterally ovariectomized through a midline abdominal
incision. In addition, a polyvinyl catheter (2 cm in length and 1 mm
in od; 1-mm tube) was inserted into one uterine horn. The catheter was
alternately inserted into left and right uterine horns. The rats were
killed at 0900 h on the fifth postoperative day.
Group 2 (n = 9). Rats underwent the same procedures as those in group 1, except that a polyvinyl catheter 4 cm in length and 3 mm in od (3-mm tube) was inserted into one uterine horn. The rats were killed at 0900 h on the fifth postoperative day.
Group 3 (n = 10). Rats underwent the same procedures as those in group 2, except that they received sc injections of 5 mg progesterone in 0.2 ml vehicle at 0900 and 2100 h on the fourth postoperative day. The rats were also killed at 0900 h on the fifth day postoperatively.
The insertion of the 3-mm tube stretched the uterine horn approximately
twice in both diameter and length compared with those of the
unstretched horn. The 1-mm tube caused very little stretch of the
uterine horn and served as a control for the presence of a foreign body
within the uterine cavity (Fig. 1
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250 g)
underwent unilateral tubal ligation through a flank incision to ensure
that they subsequently became pregnant in only one uterine horn. The
tubal ligation was performed on alternate sides. After at least 5 days
of recovery, these rats were mated with male Wistar rats, and day 1
postcoitum (pc) was designated as the morning vaginal plugs were
observed. The unilaterally pregnant rats were then randomized into four
groups. Group 1 (n = 4). On day 15 pc, sham operation was performed (i.e. midline abdominal incision was made, but no catheter was inserted) under general anesthesia, and rats were killed on day 20 pc.
Group 2 (n = 4). On day 15 pc, rats underwent insertion of a polyvinyl catheter 4 cm in length and 3 mm in od into the nongravid uterine horn through a midline abdominal incision. They were killed on day 20 pc.
Group 3 (n = 4). Rats received the sham operation as described for group 1 on day 18 pc and were killed during labor on day 23 pc. Our criteria for the presence of labor was based on delivery of at least two pups with at least one pup remaining in utero at the time the rats were killed.
Group 4 (n = 3). Rats underwent insertion of a catheter into the nongravid horn as described in group 2 on day 18 pc and were killed during labor on day 23 pc.
We observed no difference in the timing of labor in these unilaterally pregnant animals (with or without intrauterine tubes) compared with that in untreated rats in our colony.
Tissue collection
Rats were killed by carbon dioxide inhalation on the designated
days. The uterine horns were removed, placed in ice-cold saline, and
opened longitudinally. The endometrium was carefully removed by
scraping the luminal surface of the uterus using a scalpel blade. The
two uterine horns were collected separately. The myometrial tissue was
then flash-frozen in liquid nitrogen and stored in -70 C until later
analysis. Tissue from two rats in each group was also processed for
subsequent immunofluorescence localization of gap junction plaques. For
these samples, after the uterine horns were removed, a segment (3–5 mm
in length) of the central portion of the uterine horns was isolated,
rinsed in ice-cold saline, and placed in cold 4% paraformaldehyde
immediately. The remaining portions of the uterine horns were processed
as described above.
Total RNA isolation and Northern blot analysis
Myometrial tissue was pulverized in liquid nitrogen and
homogenized in 4 M guanidinium isothiocyanate at room
temperature. Total RNA was extracted from the tissues according to a
method described by Chomczynski and Sacchi (14). Twenty micrograms of
total RNA from each sample were separated in 1% agarose-3.7%
formaldehyde denaturing gel, transferred onto a nylon GeneScreen
membrane (DuPont-New England Nuclear Research Products, Boston, MA) in
0.1 M sodium phosphate over a 20-h period, and cross-linked
by UV irradiation. Northern blot analysis was carried out in a method
previously described (6). Briefly, the membrane was sequentially
hybridized to the complementary DNA (cDNA) probes of rat Cx-43 [1.3
kilobases (kb) in length corresponding to the full-length coding region
of the Cx-43 messenger RNA (mRNA) (15), a gift from Dr. David Paul,
Department of Anatomy and Cell Biology, Harvard Medical School, Boston,
MA] and rat Cx-26 [a 365-bp fragment corresponding to nucleotides
310–674 (16), generated by reverse transcription-PCR as described
previously (6)]. Probes were radiolabeled using random priming
(multiprime DNA labeling system, Amersham, Oakville, Canada) to a
specific activity of 108 cpm/µg or a final concentration
of 106 cpm/ml according to the manufacturer’s
instructions. The hybridization was carried out in a solution
containing 1% (wt/vol) BSA-0.35 M sodium phosphate-7%
SDS-30% formamide at 55 C for 20 h, followed by washes to a final
stringency of 30 mM sodium phosphate-0.1% SDS at 55 C. The
membrane was then exposed to an x-ray film (REFLECTION, DuPont-New
England Nuclear Research Products) with the aid of an intensifying
screen at -70 C for a sufficient period of time (24–72 h). To
normalize the possible loading difference, the blot was stripped with
boiled 0.1% SDS-0.1 x SSC (0.15 M sodium chloride
and 0.015 M sodium citrate) solution and then rehybridized
to a radiolabeled cDNA probe encoding an 18S ribosomal protein (a gift
from Dr. D. Denhardt, Rutgers University, Piscataway, NJ) under
hybridization conditions similar to those described above. The
autoradiograms were analyzed using a scanning densitometer (model 300A,
Molecular Dynamics, Sunnyvale, CA). The gene expression of each sample
was expressed as the ratio of the relative optic density (ROD) of the
specific gene vs. 18S. All samples for each study were
transferred onto the same blot to eliminate possible errors caused by
different hybridization conditions and to facilitate accurate
comparisons among samples.
Indirect immunofluorescence
To correlate the levels of Cx-43 mRNA expression with the
abundance of gap junction plaques formed by Cx-43, some myometrial
tissues were also subjected to indirect immunofluorescence studies.
Fresh uterine tissues were fixed in cold 4% paraformaldehyde for
2 h and then saturated with sucrose by soaking overnight at 4 C in
PBS containing 10% sucrose. The tissues were then frozen in OCT,
sectioned at 6 µm with a cryostat (Kryostat 1720, Leitz, Leica,
Germany), and overlaid on glass slides precoated with 2%
3-aminopropyltriethoxysilane in acetone. The sections were blocked in a
solution containing 5% normal goat serum, 1% BSA, 0.2% Tween-20, and
0.3% Triton X-100 at room temperature for 30 min followed by
incubation at 4 C overnight with polyclonal antibodies raised against
residues 360–382 of the rat Cx-43 protein (CT 360, a gift from Dr.
Dale Laird, Department of Anatomy, University of Western Ontario,
London, Canada) (17) diluted 1:150 in the blocking solution. After
three 5-min washes with cold PBS containing 0.2% Tween-20, the slides
were incubated with fluorescein isothiocyanate-conjugated goat
antirabbit IgG (Zymed Laboratories, South San Francisco, CA) diluted
1:150 in the blocking solution at room temperature for 1 h in the
dark. The slides were then washed three times with PBS containing 0.2%
Tween-20 and mounted with one drop of mounting media (INOVA
Diagnostics, San Diego, CA). The slides were examined under a laser
scanning confocal microscope (MRC-600, Bio-Rad Laboratories, Hercules,
CA). Adjacent sections incubated with the blocking solution alone in
the absence of the primary antibodies were used as negative controls.
In addition, sections of rat heart and liver were used as positive and
negative controls, respectively, for the presence of gap junction
plaques formed by Cx-43.
Statistical analysis
Data are expressed as the mean ± SEM. Data
were subjected to one-way ANOVA followed by all pairwise multiple
comparison procedures (Student-Newman-Keuls method) to determine
between-group differences using SigmaStat version 1.01 software (Jandel
Corp., San Rafael, CA). The level of significance for comparisons was
set at P < 0.05. Where variance was found to be
heterogeneous, the data were subjected to log transformation.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Nonpregnant studies
The insertion of 1-mm tubes in one uterine horn did not
significantly increase the level of Cx-43 mRNA compared with that in
the intact horns (0.16 ± 0.03 vs. 0.05 ± 0.01;
Fig. 2). In contrast, in rats that
received insertion of a 3-mm tube in one uterine horn, the stretched
myometrium expressed a significantly higher level of Cx-43 than the
unstretched myometrium (ROD, 0.47 ± 0.12 vs. 0.08
± 0.01; relative to 18S, P < 0.05; Fig. 2).
Administration of progesterone 24 h before tissue collection to
rats in which one uterine horn had been stretched by a 3-mm tube
blocked the increase in the Cx-43 mRNA level in the stretched horns to
a level comparable to that in the unstretched myometrium (0.09 ±
0.02 vs. 0.04 ± 0.01; Fig. 2). In contrast to Cx-43,
the expression of Cx-26 in the nonpregnant uterus was not detectable in
the ovariectomized nonpregnant myometrium and was not increased in
response to the presence of either the 1- or 3-mm tubes within
the uterine horns (data not shown).
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, D–I). The specificity of the CT 360 antibodies was demonstrated by the
specific staining of intercalated discs of the heart (Fig. 3A), with an
absence of staining found when adjacent sections were incubated in the
absence of primary antibodies (Fig. 3B). No immunofluorescence was
apparent in sections of liver (Fig. 3C), a tissue that does not express
Cx-43. All myometrial sections incubated in the absence of the primary
antibodies revealed no staining (data not shown). These data confirm
that the stretch-induced increases in Cx-43 mRNA expression were
paralleled by increases in Cx-43-containing gap junction plaques.
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). As previously reported, myometrial
expression of Cx-43 mRNA was high in the gravid uterine horns during
labor and exhibited a 4-fold increase over that found on day 20 of
gestation (Fig. 4). Unexpectedly, Cx-43 expression in the nongravid
sham-operated horns was not increased and remained at the basal levels
found during pregnancy, whereas those nongravid horns that were
stretched with a 3-mm tube exhibited a significant increase in Cx-43
expression that was similar to that found in the gravid horns.
Expression of Cx-43 in gravid and stretched horns was significantly
greater than that in nongravid, unstretched horns (14.4 ± 1.9,
15.9 ± 4.3, and 13.4 ± 4.3 vs. 4.3 ± 0.8;
P < 0.05). As in the case of the nonpregnant samples,
the density of myometrial gap junction plaques formed by Cx-43 after
uterine stretch at term increased in parallel with the increased Cx-43
mRNA expressed in these tissues (Fig. 5).
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). In contrast to Cx-43, the
presence of a 3-mm tube had no effect on the myometrial expression of
Cx-26 in either the pregnant (day 20) or laboring rat. However, the
mRNA level of Cx-26 on day 20 was significantly higher in the gravid
horn than in either of the nongravid horns (i.e. sham or
stretched; 1.2 ± 0.3 and 1.6 ± 0.2 vs. 0.24
± 0.03 and 0.7 ± 0.2, respectively). During labor (day 23) when
Cx-26 expression was low, there was no significant difference in
myometrial Cx-26 mRNA levels among any of the uterine horns.
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Discussion |
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Wathes and Porter (13) had previously reported that stretch of the ovariectomized postpartum rat uterus by a balloon increased the number of gap junctions per mm plasma membrane in the myometrium and that estrogen greatly enhanced this effect. Our data on the nonpregnant rats support these findings and further indicate that the effects of stretch are specific to Cx-43 rather than Cx-26, which is also highly expressed in the late pregnant rat myometrium. Wathes and Porter conducted their study in postpartum rats (to facilitate balloon placement) and, therefore, did not clearly discriminate between stretch acting to prevent the decline in the number of gap junctions after delivery or the induction of new gap junctions. Our demonstration of a stretch-induced increase in Cx-43 mRNA and protein levels in the ovariectomized rat myometrium (in which Cx-43 expression is either very low or absent) indicates that the effect of stretch is increased gap junction synthesis rather than a block in degradation. In addition, as placement of the 1-mm tube did not significantly increase myometrial Cx-43 mRNA and protein levels, even though it presumably had the potential to elicit a similar inflammatory response in the uterine wall, our data demonstrate that the induction of Cx-43 expression was due to myometrial stretch and not merely to the presence of a foreign body. To develop functional gap junctions, the increased level of transcription and translation of Cx-43 must be accompanied by trafficking of the protein (as connexins) to the cell membrane and the formation of aggregates of the cell-cell channels to form plaques (4). The appearance of punctate Cx-43 immunofluorescence after myometrial stretch suggests that trafficking of the Cx-43 protein to the cell membrane to form gap junction plaques occurs normally in these samples.
Data from human and animal sources indicate that there is no change in basal intrauterine or amniotic fluid pressure during pregnancy. As the law of Laplace would indicate that with increasing diameter one needs to produce an increase in wall tension to maintain intrauterine pressure, one would expect that uterine wall tension increases steadily throughout pregnancy and that this would be a stimulus to increased Cx-43 expression. Our previous data on Cx-43 expression throughout pregnancy (5) as well as the data obtained in this study reveal that this is not the case. Several possible explanations may account for this protective effect of pregnancy. Firstly, increased uterine growth during pregnancy (composed of hypertrophy and hyperplasia) may act to reduce tension on any individual myocyte. Secondly, inhibitory uterotonic agonists, such as nitric oxide, relaxin, prostacyclin, and progesterone, may reduce tension by inducing smooth muscle relaxation. Our data in nonpregnant animals also suggest that at least one of these hormones, progesterone, may act to block stretch-induced Cx-43 expression. A direct effect of progesterone is attractive, in that we have shown similar effects of progesterone on estrogen- and labor-induced Cx-43 expression in rat myometrium (19). On day 20 of pregnancy, plasma progesterone levels are high in the rat (5) and, therefore, could account for the lack of effect of stretch at this time. The rapid decline in progesterone levels at term in the rat would also explain how stretch might be able to reexert a stimulatory effect on Cx-43 expression during labor.
Previous studies, including our own (19, 20), have suggested that in the rat and other species, increased expression of CAPs (such as gap junctions and oxytocin receptor) leading to myometrial activation and labor was solely due to maternal endocrine changes (in particular an increase in the ratio of estrogen/progesterone). The data presented here suggest that this is not the case. Even though the sham-operated nongravid horn was subjected to similar systemic hormonal changes, we observed a significantly lower level of Cx-43 expression compared with that in the laboring myometrium. Although one might postulate that this low Cx-43 expression could be due to a lack of paracrine influence of the fetus or placenta, this does not appear to be the case, because the provision of stretch to the nongravid horn was sufficient in itself to induce full expression of Cx-43 during labor. However, as the same stretch stimulus had a minimal effect on Cx-43 expression on day 20, our data indicate that the expression of at least one CAP in the myometrium is under tight regulation by coordinated interactions between mechanical and hormonal factors. The observation of Wathes and Porter (13) that stretch and estrogen administration acted synergistically to increase gap junction number supports this concept.
Stretch has been recognized as a modifier of smooth muscle contractility. However, the exact mechanisms that transduce stretch into an intracellular signal, and eventually cellular responses, are poorly understood. Studies in smooth muscle other than the uterus have suggested a role for stretch-activated channels (21, 22). Stretch has also been shown to be associated with activation of a variety of signal transduction pathways, including tyrosine kinases, mitogen-activated protein kinases, protein kinase C, phospholipase C, phospholipase D, and inositol 1,4,5-trisphosphate, as well as an increase in myosin light chain phosphorylation in strips of porcine carotid artery (23, 24, 25).
Relatively few studies have been performed on the effects of mechanical stretch on myometrial contractility. In unilaterally pregnant rats, the gravid uterine horns displayed a relative depolarization of the resting membrane potential and increased smooth muscle contractile force compared with the nongravid horns (26). Coleman and Parkington (27) reported that stretching strips of uterine smooth muscle resulted in a transient depolarization in the smooth muscle cells with a time course consistent with that of the stretch-sensitive ion channels. Recently, Kasai et al (28) also demonstrated that in vitro stretch of the rat uterus caused transient smooth muscle contractions and a Ca2+ influx. However, these actions only account for immediate and transient increases in myometrial contractility induced by stretch and do not explain the increased Cx-43 expression that enables the generation of sustained, coordinated, and synchronized contractions of labor. Studies in vascular smooth muscle have shown that stretch increases expression of the transcription factor, c-fos (29). Mediation by c-fos is an attractive possibility, in that we have shown that increased expression of Cx-43 during labor is paralleled by a similar increase in c-fos and that the Cx-43 promoter contains several putative activating protein-1 sites that bind Fos/Jun. However, although c-fos expression was increased in gravid horns during labor, we found no increase in the nongravid stretched horns (unpublished data). Therefore, the mechanisms responsible for the stretch-induced increase in myometrial Cx-43 in the present report remain to be determined.
Our data on Cx-26 expression are important, in that they demonstrate the specificity of the stretch effect in relation to connexin expression. Cx-26 is highly expressed in the rat myometrium during late pregnancy at a time of rapid fetal and uterine growth. Although our data suggest that this elevated expression in not due to any stretch imposed by the growing fetus, it does appear to require the presence of the fetus and/or placenta. We had previously reported that removal of the ovary on day 17 of pregnancy blocked the normal rise in Cx-26 expression around day 20, an effect that could be reversed by treatment with exogenous progesterone (6). Furthermore, the fall in Cx-26 levels before the onset of labor could also be blocked by progesterone administration. Together, our data suggest that the ovary (possibly due to progesterone secretion) and fetal-placental unit together are required for full expression of Cx-26 in the rat myometrium. The role of Cx-26 remains to be determined. However, its temporal pattern of expression as well as the fact that its expression is regulated in a fashion opposite to that of Cx-43 raise the possibility that it acts to maintain uterine quiescence rather than promote contractility.
Our data demonstrate that differential mechanisms regulate the expression of Cx-43 and Cx-26 in the pregnant myometrium. Cx-26 expression during late pregnancy, although requiring the presence of the fetal/placental unit and elevated progesterone levels, does not require stretch of the myometrium. In contrast, Cx-43 expression during labor is dependent upon myometrial stretch under conditions of low progesterone. We speculate that the substantial increase in fetal growth that occurs in the final few days of pregnancy may provide an increased stretch stimulus, which in the endocrine environment of labor results in enhanced Cx-43 expression. Together, these data suggest that myometrial gene expression is regulated and coordinated by an interaction between endocrine and mechanical factors to an extent that was not previously recognized.
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Footnotes |
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Received May 8, 1997.
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,
estrogens, and progesterone during stretch-induced labor at term.
Prostaglandins 30:141–152[CrossRef][Medline]
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 F. Lyall, S. J. Lye, T.-G. Teoh, F. Cousins, G. Milligan, and S. C. Robson Expression of Gs{alpha}, Connexin-43, Connexin-26, and EP1, 3, and 4 Receptors in Myometrium of Prelabor Singleton Versus Multiple Gestations and the Effects of Mechanical Stretch and Steroids on Gs{alpha} Reproductive Sciences, September 1, 2002; 9(5): 299 - 307. [Abstract] [PDF]
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 J. A. Mitchell and S. J. Lye Differential Expression of Activator Protein-1 Transcription Factors in Pregnant Rat Myometrium Biol Reprod, July 1, 2002; 67(1): 240 - 246. [Abstract] [Full Text] [PDF]
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D. Minjarez, V. Konda, and R. A. Word Regulation of Uterine 5{alpha}-Reductase Type 1 in Mice Biol Reprod, November 1, 2001; 65(5): 1378 - 1382. [Abstract] [Full Text] [PDF]
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 J. R.G. Challis, S. G. Matthews, W. Gibb, and S. J. Lye Endocrine and Paracrine Regulation of Birth at Term and Preterm Endocr. Rev., October 1, 2000; 21(5): 514 - 550. [Abstract] [Full Text]
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J. E. Mesonero, Z. Tanfin, M. Hilly, P. Colosetti, J.-P. Mauger, and S. Harbon Differential Expression of Inositol 1,4,5-Trisphosphate Receptor Types 1, 2, and 3 in Rat Myometrium and Endometrium During Gestation Biol Reprod, August 1, 2000; 63(2): 532 - 537. [Abstract] [Full Text]
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J. L. Cook, D. B. Zaragoza |
