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Pregnancy |
Samuel Lunenfeld Research Institute,3 Mount Sinai Hospital, Toronto, Ontario, Canada M5G 1X5
Institute of Medical Science,4 University of Toronto, Ontario, Canada M5S 1A1
Department of Obstetrics and Gynecology,5 University of Toronto, Ontario, Canada M5S 1A1
University Health Network,6 Toronto General Research Institute, Toronto, Ontario, Canada M5G 2C4
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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gene regulation, parturition, pregnancy, progesterone, uterus
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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In most species, the end of pregnancy correlates with the rapid decline in progesterone (P4) levels. It is considered that this decrease slows down uterine growth and induces passive mechanical stretch of the uterine walls by the growing fetus/fetuses [4]. Mechanical stretch has previously been shown to promote rapid and extensive uterine hypertrophy and remodeling in nonpregnant [2, 12], unilaterally pregnant [5], and postpartum [13] animals. Studies performed on vascular SMCs indicate that mechanical forces can induce vascular remodeling and greatly influence the process of ECM synthesis [13, 14]. Moreover, the application of mechanical stimuli to other SMC types has been shown to directly influence expression of different ECM components [15, 16]
Based on these studies, we hypothesize that the biomechanical properties of the pregnant uterus are dependent on the constant synthesis of ECM components. Furthermore, we suggest that the mechanical and hormonal stimuli of pregnancy may play a role in the regulation of the ECM gene expression in uterine tissue. The regulation of the ECM constituents may also support the alterations in cellular phenotype observed at the end of pregnancy. The goal of the present study was to identify the expression pattern of the major components of myometrial ECM throughout normal pregnancy as well as to investigate the effect of both endocrine and mechanical signals on their expression. In this study, we used a rat model to investigate myometrial mRNA levels of ECM components during pregnancy, spontaneous term labor, P4-delayed labor, and RU486-induced preterm labor. Comparison of gravid and nongravid horns of unilaterally pregnant rats was undertaken to explore the influence of mechanical stretch on the expression of ECM genes.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Wistar rats (Charles River Co., St. Constance, PQ, Canada) were housed individually under standard environmental conditions (12L:12D cycle) and fed Purina Rat Chow (Ralston Purina, St. Louis, MO) and water ad libitum. Female virgin rats were mated with male Wistar rats. Day 1 of gestation was designated as the day a vaginal plug was observed. The average time of delivery under these conditions was during the morning of Day 23. Our criteria for labor were based on delivery of at least one pup. The Samuel Lunenfeld Research Institute Animal Care Committee approved all animal experiments.
Experimental Design
Normal pregnancy and term labor Animals were killed by carbon dioxide inhalation and myometrial samples were collected on Gestational Days 0 (nonpregnant, NP), 12, 15, 17, 19, 21, 22, 23, or 1 day postpartum (1PP). Tissue was collected at 1000 h on all days with the following exceptions: on Day 22, an additional sample (Day 22pm) was collected at 2300 h; on Day 23, a not-in-labor (Day 23NIL) sample was collected at 1800 h; while the labor (Day 23L) sample was collected once the animals had delivered at least one pup (n = 3).
Progesterone-delayed labor To determine whether high plasma levels of P4 might modulate the expression of ECM proteins, pregnant rats were randomized to receive daily subcutaneous injections of either P4 (16 mg/kg in 0.2 ml corn oil containing 10% ethanol; Sigma, St. Louis, MO) or vehicle starting on Day 20 of gestation. Animals (n = 3 at each time point for each treatment) were killed on Days 21, 22, or 23 (during labor) in the vehicle-treated group or Days 21, 22, 23, or 24 in the P4-treated group.
RU486-induced preterm labor On Day 19 of gestation, two groups of rats were treated with either RU486 (10 mg/kg, s.c., 1000 h, in 0.5 ml corn oil containing 10% ethanol, Mifepristone; 17ß-hydroxy-11ß-[4-dimethylaminophenyl]-17-[1-propynyl]-estra-4,10-dien-3-one; Sigma) or vehicle. Myometrial samples were collected from both groups of animals on Day 20 when the RU486-treated animals had delivered at least one pup (n = 4).
Unilaterally pregnant rats Under general anesthesia, virgin female rats underwent tubal ligation through a flank incision to ensure that they subsequently became pregnant in only one horn [17]. Animals were allowed to recover from surgery for at least 7 days before mating. Pregnant myometrial samples from empty and gravid horns were collected on Days 15, 17, 19, 21, 22, 23, or 1PP (n = 3).
Tissue Collection
Uterine horns were placed into ice-cold PBS, bisected longitudinally, and dissected away from both pups and placentas. The endometrium was carefully removed from the myometrial tissue by mechanical scraping on ice, which we have previously shown removes the entire luminal epithelium and the majority of the uterine stroma [18]. The myometrial tissue was flash frozen in liquid nitrogen and stored at -70°C.
Complementary DNA Probes
Probes for rat fibronectin (GenBank X15906), elastin (GenBank NM_007925), laminin ß2 (GenBank NM_012974), and collagen III 
1 (GenBank X70369) were generated by PCR using the following primers: fibronectin upper 5' TAT GAC GAC GGG AAG ACC TA, fibronectin lower 5' AGA CGG CAA AAG AAA GCA G, elastin upper 5' GCC AAA TAC GGA GCC AGA GG, elastin lower 5' AAC ACC AGC CCC ACC AAG AAG TC, collagen III 1 upper 5' AAT TGC AGG GCT AAC TGG AG, collagen III 1 lower 5' AGC CCT CAG ATC CTC TTT CA, laminin ß2 upper 5' CGG GTG TTT TTC CTG CTT G, laminin ß2 lower 5' CGG GTA TCT GCT GAG TTG CT. The following probes were provided by other research labs: mouse collagen IV (1) cDNA and human procollagen I (1) cDNA (Dr. M. Post, Hospital for Sick Children, Toronto, ON, Canada) and 18S ribosomal protein (Dr. Denhardt, Rutgers University, Piscataway, NJ).
Northern Blot Analysis
Frozen tissue was crushed under liquid nitrogen using a mortar and pestle. Total RNA was extracted from the tissues using TRIZOL (Gibco BRL, Burlington, ON, Canada) according to manufacturer's instructions. RNA samples (10 µg) were denatured in formamide/formaldehyde/MOPS for 15 min at 65°C and separated on 1% (wt/vol) agarose (Gibco BRL) gel containing 3.7% (vol/vol) formaldehyde (J.T. Baker, Phillipsburg, NJ) in MOPS (3-[N-morpholino]propanesulfonic acid; Sigma). The RNA was transferred in 0.1 M sodium phosphate (NaP; Sigma) onto a nylon membrane (GeneScreen, DuPont, NEN Research Products, Boston, MA) by capillary action and cross-linked by ultraviolet irradiation. The cDNA probes were labeled with [-32P] deoxycytosine triphosphate (NEN Research Products, Boston, MA) using the multiprime DNA labeling system (Amersham Biosciences, Little Chalfont, UK). Hybridization was conducted at 55°C in 30% formamide (vol/vol) for 20 h according to the method described in Bio-Rad bulletin 1110 (Bio-Rad Laboratories, Richmond, CA). Blots were washed at 55°C to a final stringency of 30 mM NaP/0.1% SDS (wt/vol) (EM Science, Darmstadt, Germany). All RNA isolation and analysis was carried out in diethyl pyrocarbonate (Sigma) water. Probed membranes were exposed to x-ray film (Kodak XAR, Eastman Kodak, Rochester, NY) with an intensifying screen at -70°C and analyzed by densitometry. Blots were stripped in boiling 0.1 x SSC/0.1%SDS (wt/vol) before subsequent reprobing with similarly labeled 18S probe.
Statistical Analysis
Gestational profiles were subjected to a one-way ANOVA followed by pairwise multiple comparison procedures (Student-Newman-Keuls method) to determine differences between groups. Progesterone (Days 21, 22, and 23) and tubal-ligation data were analyzed by two-way ANOVA followed by pairwise multiple comparison procedures as described above. The Day-24 progesterone-treated group was compared with the Day-23 vehicle group using a t-test. RU486 results were compared with vehicle using a t-test. Where required, the data was transformed by the appropriate method to obtain a normal distribution. Statistical analysis was carried out using SigmaStat version 1.01 (Jandel Corp., San Rafael, CA) with the level of significance for comparison set at P < 0.05.
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RESULTS |
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All cDNA probes used for Northern blot analysis hybridized to transcripts of the appropriate sizes for ECM genes. The elastin probe (ELA) detected a major signal at 3.5 kilobase (kb) while the laminin ß2 (LAM) and fibronectin (FBN) probes detected signals at 5.6 and 7.9 kb, respectively. Two signals were detected for procollagen I (1) (COL I) (5.8 and 4.8 kb), procollagen III (COL III) (5.4 and 4.8 kb), and collagen VI (1) (COL VI) (6.4 and 5.4 kb). The 18S band was detected at 1.9 kb.
Northern blot analysis and densitometric quantitation demonstrated extremely low basal expression of all ECM mRNAs in nonpregnant rat myometrium (Fig. 1). Statistical analysis showed an overall significant effect of gestational age on expression of ECM proteins in rat myometrial tissue. Pregnancy caused a dramatic increase in ELA mRNA abundance by midgestation, and the high level of gene expression was maintained throughout the second half of gestation (48.1-fold increase from Day 12 until Day 22 comparing with NP sample, P < 0.001). On the day of labor, ELA mRNA levels decreased slightly (34.1-fold increase on Day 23L versus NP) and displayed a further dramatic decrease 1 day postpartum (1PP), returning to nonpregnant levels. Levels of COL I mRNA increased progressively in pregnant uterine tissue, reaching a peak by Day 17 (20.5-fold increase versus NP, P < 0.001), then decreased gradually and returned to the nonpregnant level on 1PP. COL III gene expression demonstrated a similar pattern to COL I, being expressed evenly throughout the second part of gestation, with the highest level on Day 19 (24.9-fold increase versus NP, P < 0.05). In contrast, densitometric analysis revealed that myometrial levels of FBN mRNA remained low throughout most of gestation but showed a dramatic increase by Day 22, a further increase to peak levels at Day 23L (164.4-fold increase versus NP, P < 0.001) (Fig. 1) and a subsequent sharp reduction on Day 1PP. The components of the BM, LAM, and COL IV displayed a similar expression profile to FBN, except that LAM mRNA levels were elevated slightly earlier in pregnancy (16.9-fold increase on Day 17 versus NP, P < 0.05) while COL IV mRNA levels remained low until Day 21. The levels of both LAM and COL IV mRNA increased significantly on Days 22 and 23 (35.8-fold increase for LAM and 26.4-fold increase for COL IV versus NP, P < 0.05) and remained elevated even on Day 1PP (Fig. 1).
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Effect of Progesterone on ECM Expression at Term
In this study, animals treated from Day 20 with daily injections of P4 failed to initiate labor on Day 23 and did not show the expected increase in expression of FBN and LAM mRNA (Fig. 2). While there was no significant difference between the control and P4-treated groups on Day 21 (1 day after injection), FBN and LAM mRNA levels in rats treated with hormone were significantly lower on Day 22 (relative optical density [ROD] 1.64 ± 0.56 [mean SEM] versus 0.52 ± 0.27 for FBN and 1.53 ± 0.17 versus 0.62 ± 0.25 for LAM, P < 0.05) and Day 23 (ROD 2.3 ± 0.51 versus 0.92 ± 0.28 for FBN and 2.16 ± 0.55 versus 0.75 ± 0.32 for LAM, P < 0.05) compared with the control group. Moreover, the mRNA levels of LAM and FBN in P4-treated rats remained low on Day 24 compared with that in vehicle-treated animals on Day 23 (laboring sample) (P < 0.05). In addition, the administration of P4 prevented the fall of COL III mRNA levels on Day 23 (ROD 1.3 ± 0.14) and Day 24 (ROD 1.58 ± 0.65) as seen in vehicle-treated animals on Day 23 (ROD 0.58 ± 0.17, P < 0.05 for both) (Fig. 2). The levels of COL IV, COL I, and ELA were unaffected by P4 treatment. These results demonstrate that artificial maintenance of elevated P4 levels in pregnant rats prevents the normal term induction of LAM and FBN and the reduction in COL III genes.
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ECM Expression During RU486-Induced Preterm Labor
Treatment of rats at Day 19 of gestation with the P4 receptor antagonist, RU486, induces preterm labor within 24 h [17]. Analysis of myometrial tissue collected from vehicle and RU486-treated rats indicated that mRNA levels of FBN, COL IV, and LAM were significantly elevated after RU486 treatment (Fig. 3A). Northern blot analysis revealed that RU486 treatment caused a dramatic, significant increase in expression of FBN mRNA (18.5 ± 2.5-fold), COL IV (2.64 ± 0.38-fold), and LAM (3.14 ± 0.67-fold) in pregnant rat myometrium compared with the vehicle sample (Fig. 3A). In contrast, the mRNA levels of structural proteins (COL I, COL III, and ELA) were unaffected by RU486 treatment (Fig. 3B). The data indicate that an abrupt decrease in P4 plasma levels caused by RU486 leads to an induction of FBN, LAM, and COL IV genes.
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Gravidity Modulates the Expression of Extracellular Matrix Genes in Unilaterally Pregnant Rat Myometrium
Analysis of the uterine tissue from empty and gravid horns revealed that the expression of all six matrix components were generally much lower in empty horns as compared with the gravid horns of unilaterally pregnant rats. Densitometric analysis indicated a dramatic induction of the ELA gene in the gravid horn compared with the empty horn from Day 15 of gestation until Day 23 (11.8 ± 5.2-fold increase, P < 0.001 for all gestational days) and a dramatic decrease in mRNA level on 1PP to levels equivalent to those detected in the empty horn (Fig. 4). Although transcript levels of fibrillar COL (types I and III) were lower in nongravid than gravid horns, the expression of both COLs increased progressively in both horns, reaching a peak on Day 17 of pregnancy (2.25-fold increase in a gravid horn versus empty horn, P < 0.001), then decreased gradually, and returned to the nonpregnant levels by 1PP (Fig. 4). FBN mRNA was expressed at very low levels in the empty horn of unilaterally pregnant rats throughout pregnancy. Expression of FBN in the gravid horns was low at early gestational days (Days 15–19), increased dramatically on Day 22, peaked on Day 23 during labor (20-fold increase in gravid versus empty horn, P < 0.001), and decreased on 1PP (Fig. 4). Expression of LAM and COL IV was significantly elevated (P < 0.05) in the gravid horns starting from Day 15 for COL IV and from Day 17 for LAM, as compared with the corresponding empty horns (Fig. 4).
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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The presence of P4 is required in virtually all species in order to maintain pregnancy [24]. In rats, P4 levels in maternal serum peak between Day 15 and Day 19 and then decrease dramatically until Day 23, the day of delivery [25]. This decrease in P4 and the subsequent increase in estrogen results in an increase in the estrogen to progesterone ratio (E:P) and is thought to lead to the activation of a number of genes involved in the induction of labor [17]. Interestingly, in this study, we show that the expression levels of COL type I and type III correlate with gestational changes in the plasma E:P ratio (Figs. 1 and 4), suggesting the hormonal regulation of both genes. In support of this assumption, aortic SMCs cultured in the presence of 17ß-estradiol have been demonstrated to display a decreased production of COL, in addition to altering the ratio of type I and III COL fractions [26]. Moreover, in rat uterine tissue, the addition of exogenous P4 inhibited collagenase expression [27], reduced collagenolytic activity, and increased collagen content [28]. These data raise the possibility that P4 modulates uterine tissue remodeling, resulting in an altered balance of expression of different ECM components. Our data indicate that P4 is clearly involved in the regulation of a number of ECM genes and can both stimulate (fibrillar COLs) and inhibit (BM components) ECM production in the uterus.
Mechanical stretch of the myometrium has been shown to induce the expression of genes involved in the onset of labor [17, 18, 29–31]. Mechanical stretch has also been shown to regulate the expression of ECM components in pulmonary artery, fetal lung cells, and bladder SMCs [15, 16, 32]. Distention of the nonpregnant uterine horn by wax injection resulted in a considerably greater weight and increase in collagen formation [2]. Using a unilaterally pregnant rat model, Goldspink and Douglas showed that uterine protein content was dramatically increased in the gravid horn (subjected to stretch by the growing fetus), while remaining unchanged in the empty horn [5]. Using the same model, we found that the gestational changes in ECM gene expression described in this study occurred near term specifically in the gravid horn and not in the empty horn of unilaterally pregnant rats. Our results indicate a synergistic action of endocrine and mechanical signals on myometrial ECM expression during pregnancy. Using both in vivo and in vitro rat models, we have previously shown a coregulation of activator protein-1 (AP-1) gene expression by hormonal and mechanical factors [30, 31, 33]. Moreover, in an in vitro system, the magnitude of the stretch response was found to depend on the presence of particular ECM components [31]. Interestingly, LAM, COL, ELA, FBN, and matrix remodeling enzymes contain AP-1 sites in their promoter regions and may therefore be regulated by AP-1 proteins (review in [30]). This raises the intriguing possibility that AP-1 transcription factors may serve as regulatory proteins during pregnancy, capable of mediating the mechanical responsiveness of the ECM genes.
There is extensive evidence showing that vascular SMCs are phenotypically modified in the progression of a variety of vascular diseases, including atherosclerosis, postangioplasty restenosis, and hypertension [34, 35]. SMCs within atherosclerotic lesions exhibit marked differences in morphology and protein expression patterns as compared with normal vascular SMCs. These changes have collectively been referred to as phenotypic modulation from a contractile-differentiated to synthetic-dedifferentiated state. In the synthetic state, SMCs proliferate but are unable to contract. Changes in integrin expression occur during phenotypic modulation; therefore, it has been suggested that the ECM may be one of the determinants of the SMC phenotype [34]. We hypothesize that, during early pregnancy, myometrial SMCs change their phenotype from a contractile to a synthetic state and start to proliferate. As pregnancy proceeds under the influence of high progesterone levels, mechanical tension induces myometrial growth and remodeling, which results from myocyte hypertrophy and an increased synthesis of interstitial matrix proteins. By the end of gestation, as a result of the loss of progesterone domination, the cells of the myometrium switch from a synthetic to a contractile phenotype. This is characterized by a dramatic increase in BM matrix synthesis (laminin and collagen IV), a cessation of myocyte hypertrophy and interstitial matrix synthesis (specifically, COL I and COL III), and likely an increase in production of contractile proteins. Increased expression of the BM proteins near term may stimulate the restitution of a differentiated contractile phenotype of myometrial SMCs, which is necessary for uterine contraction during labor. The role of P4 is underlined in this study by the observation that major changes in ECM gene expression, which may potentially cause the switch from a synthetic to a contractile phenotype, can be blocked at term by the administration of P4. Likewise, the change in ECM production caused by P4 withdrawal alters the ability of the cell to sense tension and respond to mechanical stimulation. A detailed analysis of the signals transduced from the matrix and uterine cellular microenvironment will provide a better understanding of the factors that determine the phenotypic modulation of uterine myocytes in vivo and may lead to the discovery of ways to treat disorders of pregnancy associated with inadequate production of ECM components.
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FOOTNOTES |
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2 Correspondence: Stephen J. Lye, Samuel Lunenfeld Research Institute at Mount Sinai, 600 University Avenue, Suite 870, Toronto, Ontario, Canada M5G 1X5. FAX: 416 586 8740; lye{at}mshri.on.ca
Received: 29 September 2003.
First decision: 24 October 2003.
Accepted: 24 November 2003.
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REFERENCES |
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