Molecular Human Reproduction, Vol. 8, No. 6, 559-565,
June 2002
© 2002 European Society of Human Reproduction and Embryology
Uterine physiology |
Elastin distribution in the myometrial and vascular smooth muscle of the human uterus
1 Departments of Obstetrics and Gynaecology, University of Glasgow, Glasgow Royal Infirmary, 10 Alexandra Parade, Glasgow G31 2ER, 2 University of Southampton, Princess Anne Hospital, Coxford Road, Southampton SO16 5YA and 3 Department of Pathology, Glasgow Royal Infirmary, Castle Street, Glasgow G4 OSF, UK
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Abstract |
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Magnetic resonance imaging and transvaginal ultrasonography in women of reproductive age suggest that the myometrium consists of inner and outer layers. It was hypothesized that these structural and functional differences in the myometrium might be associated with a variation in elastin distribution. Fifty-one hysterectomy specimens representing all phases of the normal menstrual cycle were studied by immunocytochemistry, orcein staining and image analysis. Elastin was present within the outer myometrial smooth muscle, but was less widely distributed in the inner smooth muscle. Immunoreactivity and staining were observed in the myometrial arteries and arterioles and within the basal portions of endometrial arterioles. Elastin was also present in perivascular tissue, particularly near the large vessels. More extravascular (i.e. perivascular and smooth muscle) elastin was present in the outer myometrium in all cases, although no distinct layering was observed. Semi-quantitative analysis of the elastin distribution in 11 full thickness specimens demonstrated a decreasing gradient from outer to inner myometrium rather than distinct layering. Contrary to previous reports, these data suggest that the external region of the myometrium is more elastic than the inner region and that elastin is found throughout the arteriolar tree of the human uterus.
elastin/image analysis/immunocytochemistry/myometrial gradient/uterus
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Introduction |
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The human uterus is a pear-shaped organ, the gross morphology of which is determined by the nature of the myometrial smooth muscle coat. This muscle coat undergoes dramatic remodelling during pregnancy in order to accommodate the growing fetus. The uterus would appear to have specific features that are not observed in other adult organs, which allow this degree of remodelling. It has been postulated, for example, that the highly coiled nature of the myometrial arteries is designed to permit expansion of the myometrial smooth muscle as it hypertrophies during pregnancy (Farrer-Brown et al., 1970a
,b).
In histological sections, the human myometrium is a continuous layer of smooth muscle cells organized in large interwoven bundles (Ramsey, 1994). This pattern is distinct from the circular and longitudinal layering of the myometrial smooth muscle observed in other species such as the mouse, which has a bicornuate uterus (Garfield and Yallampalli, 1994). Despite the lack of distinct morphological layering in the human uterus, evidence has emerged of distinct inner and outer zones. T2-weighted spin echo magnetic resonance imaging (MRI) suggests the existence of a distinct inner layer within the human myometrium, although the precise significance of this observation remains unclear (Brown et al., 1991; Scoutt et al., 1991). Histological analysis of Feulgen-stained nuclei, undertaken as part of a study involving MRI, demonstrated that the total nuclear cross-sectional area is greater within the inner myometrium, suggesting that MRI may be associated with a structural difference in the muscle (Scoutt et al., 1991). Time-lapse observations of transvaginal ultrasound recordings show that there is also a functional difference between the inner and outer myometrium (de Vries et al., 1990; Lyons et al., 1991; Chalubinski et al., 1993; Kunz et al., 1996; Brosens et al., 1998). Peristaltic waves emanate from the inner layer and vary in amplitude, direction and frequency during the course of the menstrual cycle.
There is a need to understand how functional layering within the non-pregnant myometrium can be accommodated with the ability to distend during pregnancy. Elasticity within distensible tissues such as elastic arteries and the lung is associated with the presence of elastic fibres in the extracellular matrix (Rosenbloom et al., 1993). These fibres form filaments, laminae or a three-dimensional honeycomb depending on the tissue in which they are located (Mecham and Davis, 1994). Within the human uterus, scanning electron microscopy of the extracellular matrix left behind after chemical extraction has revealed a sponge-like matrix containing thin flat sheets or lamellae (Leppert and Yu, 1991). The relative abundance of elastin increases during gestation, presumably to accommodate the physical strain of pregnancy within the uterine muscle, and then declines in the post-partum period (Gunja-Smith and Woessner, 1985; Stone and Franzblau, 1995).
Mature elastic fibres that impart elasticity consist of two morphologically distinct components, an abundant amorphous material containing elastin and a microfibrillar component, which is present around the periphery of the amorphous material and also to some extent interspersed within it (Rosenbloom et al., 1984; Rosenbloom, 1993; Vrhovski and Weiss, 1998). The amorphous material is formed from the soluble precursor molecule tropoelastin, which becomes cross-linked to form an elastic matrix that is capable of being stretched and undergoing elastic recoil (Rosenbloom et al., 1993; Mecham and Davis, 1994). The microfibrilar component contains fibrillin, microfibril-associated glycoproteins and a range of other extracellular matrix proteins (Brown-Augsburger et al., 1996; Gibson et al., 1998; Sasaki et al., 1999).
The aim of this study was to determine whether the non-pregnant uterus has a distribution of elastin that might either facilitate stretching of the uterine smooth muscle or vascular system, or be associated with myometrial layering. Immunocytochemical localization of elastin was used to study the distribution of elastic components in the human endometrium and myometrium.
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Materials and methods |
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Tissue collection and processing
Endometrial and myometrial specimens were obtained from 51 women undergoing hysterectomy for benign conditions at Glasgow Royal and Western Infirmaries and the Southern General Hospital, with the permission of the local ethics committees and the written and informed consent of the patients. Forty-eight of these women were parous. The tissue was fixed in 10% (w/v) buffered formaldehyde (Chemix, Standish, Wigan, UK) for 24h and then wax embedded. Tissues were examined for evidence of pathological abnormality and stage of the menstrual cycle using standard histological criteria. Only tissue devoid of uterine fibroids was studied. Additional specimen blocks, examined independently within the pathology departments, were also found to lack abnormality. Sufficient myometrium was present on 40 specimens [12 proliferative, 10 secretory, five menstrual and 13 where the woman had received treatment with a levonorgestrel-releasing intrauterine system (LNG–IUS); Mirena®] to allow analysis of elastin distribution. In the remaining 11 specimens (two proliferative, three secretory, two menstrual, one inactive, one post-menopausal and two LNG–IUS treated) only the endometrium was used for the present study. The duration of exposure to intrauterine LNG was 1–48 months.
Immunocytochemistry and orcein staining
Elastin was localized using the BA-4 monoclonal anti-elastin antibody (Sigma), which was raised against bovine 
-elastin. The antibody recognizes the chemotoactic hexapeptide epitope chemotactic epitope also found within the human elastin peptide sequence (Wrenn et al., 1986; Indik et al., 1987).
Sections were pre-treated with a 0.01 mol/l HCl pH 2.5 solution containing 2–10 µg/ml pepsin for 30 min at 37°C (Sigma-Aldrich, Poole, UK). The enzyme digestion was stopped by washing twice in distilled water for 5 min. The tissues were then pre-incubated with 20% (w/v) normal horse serum plus 20% normal human serum in phosphate-buffered saline (PBS) for 30 min at room temperature and incubated overnight at 4°C with 5 µg/ml of anti-elastin antibody in 2% normal horse serum. The sections were washed in PBS twice before incubation for 30 min at room temperature with biotinylated anti-mouse immunoglobulin (Vector Laboratories, Peterborough, UK), diluted (1:200) in 2% normal horse serum and 5% normal human serum. Antibody binding was detected with the ABC immunoperoxidase detection system (Elite ABC Kit®; Vector). Orcein staining (Wilhelm et al., 1999) was undertaken to verify the immunolocalization.
Vascular endothelium was identified after microwave pretreatment with a monoclonal antibody to CD31 (Dako, Ely, Cambs, UK), using the same detection system. Negative control slides in which no primary antibody was used were included. No enzyme reaction product was observed in these control slides.
Microscopy section scanning and image analysis
Sections were examined by brightfield microscopy (BX 50; Olympus) and digital images were captured from a 3-CCD colour camera (JVC). Low magnification images of the whole specimen were obtained by direct scanning of the sections (Coolscan; Nikon). Additional sections of full thickness endometrial and myometrial tissue (n = 11), where elastin had been localized without haematoxylin counterstaining, were scanned at a resolution of 2700 dpi using uniform exposure and gamma settings. The images were spatially calibrated using a 35 mm photograph of a stage micrometer. The blue channel of the tissue images was selected to produce an 8-bit monochrome image with suitable density information. A rectangular area of tissue extending from the serosal surface to the endometrium was manually selected using the area of interest tool within an image analysis program (ImagePro Plus; Media Cybernetics). The position of the endometrial boundary was noted by annotation on a copy of the image. These areas were chosen to minimize mechanically-induced sectioning artefacts and not on the basis of density. The average image intensity across the width of the rectangle was calculated for each pixel row (ImagePro Plus). The density of the resulting line profile was expressed in arbitrary units (0–255 inverted image grey level values). An estimate of the variation in elastin distribution throughout the thickness of the myometrium was obtained by averaging the data from 11 high quality specimens. The data from these specimens was averaged so that comparisons could be made between specimens despite differences in myometrial sectional thickness (18–28 mm) or experimental variations in elastin localization or specimen scanning.
In order to normalize the specimens by width, the data from each scan were divided into an equal number of slices (n = 93, 219–300 µm width) and a local mean was calculated for each slice. The mean values for each slice were then averaged over all specimens. As the procedure involved dividing the sections into slices, the slight smoothing effect of calculating a consecutive average was introduced. In practice, this was restricted to removing very narrow spikes in the data even where the broadest slice width was used. The data were then rescaled by density before averaging so that the peak density value in each scan was equivalent. Multiplicative correction factors of 1–1.43 were used for rescaling the density values.
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Results |
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Elastin was immunolocalized in paraffin-embedded sections (n = 51) from all stages of the menstrual cycle (14 proliferative, 13 secretory, seven menstrual, one inactive, one postmenopausal, 15 LNG–IUS).
Elastin within the endometrium
Forty sections were used for endometrial observations (11 proliferative, 11 secretory, three menstrual, 15 LNG–IUS).
Within the human endometrium, elastin was present in the basal portions of the spiral arterioles (Figure 1A,B). No elastin was found in the more superficial parts of the vascular tree or in the endometrial stroma, surface epithelium or glandular basement membrane of the normal endometrium (Figure 1C,D). Despite the absence of elastin in the stroma, 78% (95/122) of cross-sections of basal lymphoid aggregates had traces of elastin. Elastin was absent from the larger thin-walled vessels (venules) in which the endothelium was identified with an antibody to CD31 (Figure 1E,F).
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Elastin distribution within the myometrium
Microscopic examination of sections where sufficient myometrial thickness was available for assessment (n = 40, 12 proliferative, 10 secretory, five menstrual, 13 LNG–IUS) revealed that elastin was absent or of low abundance in the inner smooth muscle of the myometrium, although the walls of the myometrial arteries were immunoreactive (Figure 2A
). Elastin was present in perivascular tissue, particularly near the large vessels of the outer myometrium (Figure 2B). In the outer myometrium, elastin was also located within the smooth muscle (Figure 2C,D). More perivascular and extravascular elastin was present in the outer myometrium compared with the inner myometrium in all cases.
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Additional sections were stained with orcein and intense staining was observed in the spiral arterioles (Figure 3A,B
) and in large and small arteries of the inner and outer myometrium (Figure 3B,C). Extravascular staining was observed in the outer myometrium (Figure 3C). The areas of highest intensity (Figure 3B,D) showed a similar distribution to the elastin immunolocalization.
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Progestagen exposure and elastin distribution
There was no obvious difference in the myometrial distribution of elastin after exposure to intrauterine levonorgestrel. Elastin was also present within the basal portions of the spiral arterioles of the 15 endometria examined. In one specimen, elastin was present in some arterioles but absent in others. In three specimens, elastin was widely distributed in the basal stroma (not shown).
Semi-quantitative measurement of elastin distribution
Qualitative observation of the myometrium suggested the existence of a gradient of elastin distribution in 36 of the 40 specimens (Figure 4). Semi-quantitative examination of the elastin distribution in 11 good quality full thickness specimens (one proliferative, four secretory, two menstrual and four LNG–IUS treated) showed considerable variability between specimens (Figure 5). When the normalized average elastin density was calculated, a higher density of elastin was present in the outer compared with the inner myometrium (Figure 6).
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Discussion |
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TopAbstractIntroductionMaterials and methodsResultsDiscussionAcknowledgementsReferences |
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Qualitative observation of elastin distribution in the non-pregnant uterus revealed a decreasing gradient of this extracellular matrix component from the outer towards the inner myometrium, and the presence of elastin in the endometrial arterioles. These observations applied throughout the menstrual cycle and after exposure to an intrauterine progestagen. This conclusion was supported by qualitative inspection of 40 wax-embedded specimens.
Although the gradient was consistently observed, there was great variability between individuals in the pattern that was present. This variability might have arisen due to natural differences in myometrial width and also as a result of differences in elastin expression. In addition, technical artefacts such as variations in section orientation or immunocytochemical procedure would have contributed further variability, although these could not have changed the trend consistently observed within individual sections.
In contrast to the present study, McCarthy and colleagues, undertaking an MRI examination of the myometrial properties and water content in human uteri, reported that elastin distribution did not differ between the `junctional zone' (inner myometrium) and the adjacent myometrium (McCarthy et al., 1989). The experience of the present authors suggests that the use of a less specific histochemical stain in that study, instead of immunocytochemistry, would have made detection of the gradient more difficult.
Within the endometrium, elastin was shown to be restricted to the basal portion of the endometrial arterioles. The presence of elastin within the arterioles suggests that the development of the arteriolar wall may have even greater temporal and spatial complexity than was previously postulated (Kohnen et al., 2000). This finding contrasts with those of Fleming and Bell who reported that the human endometrium did not contain elastin (Fleming and Bell, 1997). In their study, endometrial specimens were collected from regularly cycling women undergoing curettage or hysterectomy. If the results of that study were based largely on curettings with little basal endometrium, it is possible that elastin in the basal tissue was not observed.
Following treatment with the LNG–IUS, there were no obvious differences in the distribution of elastin within the smooth muscle, arterial walls and perivascular tissue compared with untreated patients. Elastin was present in the basal portion of the endometrial arterioles after exposure to the LNG–IUS. In three out of 12 specimens, elastin was also present in the basal endometrial stroma. Kohnen et al. reported that some stromal cells of the basal endometrium produce -smooth muscle actin and thus have a myofibroblastic phenotype (Kohnen et al., 2000). It is possible that treatment with exogenous progestagen in some patients makes these myofibroblasts elastogenic.
Qualitative observations suggest that the myometrial gradient has three tissue components; vessel walls, perivascular tissue and myometrial smooth muscle (Figure 7). Within the inner myometrial smooth muscle, elastin was absent or of low abundance, whereas in more superficial parts of the tissue, close to the serosal surface, elastin was observed in the smooth muscle of areas remote from arterioles and larger blood vessels. The gradient within the smooth muscle cells of the myometrium suggests a phenotypic difference between the smooth muscle cells of the inner and outer myometrium, which requires further characterization.
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Perivascular tissue might represent a second important component of the gradient. This is particularly the case in the outer part of the endometrium where perivascular elastin is associated with larger calibre vessels. The current observations suggest that the highly coiled arcuate arteries and the outer segments of the radial arteries are embedded in a perivascular elastic matrix. By contrast, only traces of elastin were observed in the inner myometrium in areas surrounding the larger of the arterioles and sometimes close to the thin-walled vessels (veins). Perivascular elastin may therefore have been a relatively minor component of the gradient in the inner myometrium, but may have contributed significantly to the measurements taken within the outer part of the tissue.
The third component of the elastin gradient is the blood vessel wall. Changes in the total cross-sectional area of veins and arteries between inner and outer myometrium or in the nature of the vessels themselves could have a substantial effect on the average pattern. If it can be assumed that luminal diameter and vessel wall thickness are positively related, the microradiographs of Farrer-Brown et al. suggest that there is a gradient in the total arteriolar cross-sectional area (Farrer-Brown et al., 1970a,b). Unfortunately it would not be possible to measure the individual components of the gradient using the current methods.
Elastin within the uterus could provide a dynamic function during pregnancy by allowing the uterus to enlarge so that it can accommodate the growing fetus. The need to permit stretch is shared by other tissues and organs such as the elastic arteries (Shadwick, 1999), bladder (Murakumo et al., 1995) and respiratory tract (Starcher, 2000). However, in the non-pregnant situation the uterus, unlike the organs mentioned above, does not experience an internal dilating force. Indeed, uterine contraction associated with menstruation, for example, will produce compaction rather than stretch. The role of the elastic components is therefore more likely to assume greater importance during pregnancy and parturition, when elastin may help to accommodate a slowly increasing strain and as pregnancy proceeds might help to contain fetal movement. Gunja-Smith and Woessner reported that during pregnancy the elastin content increases 4- to 5-fold (although it is less cross-linked), and that in non-gravid uteri the elastin content increases with parity (Gunja-Smith and Woessner, 1985).
Farrer-Brown et al. postulated that the tortuosity of the myometrial arteries is designed to allow expansion of the gravid uterus, which would otherwise be subject to excessive tension (Farrer-Brown et al., 1970a,b). The spiral nature of the arteries might therefore reduce the force required to produce linear elongation. This hypothesis is consistent with the fact that the less muscularized, thinner-walled venous system does not show similar spiral morphology (Farrer-Brown et al., 1970b). The present finding of elastin within the smooth muscle and perivascular tissue suggests that the surrounding tissue, as well as the vascular system, has a specific adaptation that facilitates stretch. It is clear that the arteries assume a tortuous course because the length of the arteries is greater than that of the equivalent linear dimension of the surrounding tissue. However, as most of the uteri that become available for research after hysterectomy are taken from parous women it may be that the vessel length has already been modified as a consequence of pregnancy prior to examination.
If the distending force experienced during pregnancy is resolved within the outer part of the muscle it may be more appropriate for the outer part to contain a higher abundance of elastic components. It may, however, be equally relevant to ask why the inner myometrium is less elastic. Several studies (de Vries et al., 1990; Lyons et al., 1991; Chalubinski et al., 1993; Kunz et al., 1996, Brosens et al., 1998) have demonstrated myometrial peristalsis in the human uterus during the course of the menstrual cycle. These waves emanate from the inner and not the outer myometrium. The present data suggest that the non-peristaltic tissue (outer myometrium), as well as containing large calibre vessels, is also more elastic than the inner myometrium. The reduced distribution of elastin present in the inner myometrium might facilitate a more efficient propagation of peristaltic waves in the non-pregnant uterus.
In conclusion, the present results suggest that there is a gradient of elastin distribution in the uterus and lead us to postulate that the inner myometrium might be less elastic than the outer myometrium.
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We thank the patients, gynaecologists and pathologists at Glasgow Royal Infirmary, the Western Infirmary and the Southern General Hospital for their invaluable assistance during the course of this study. K.R. was in receipt of a Wellcome Trust Vacation Scholarship. The salary of C.J.M. was provided by an educational grant from Schering UK.
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4 To whom correspondence should be addressed. E-mail: steven.campbell{at}udcf.gla.ac.uk
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References |
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Submitted on September 10, 2001; accepted on March 1, 2002.
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