Mol. Hum. Reprod. Advance Access originally published online on July 26, 2006
Molecular Human Reproduction 2006 12(9):525-534; doi:10.1093/molehr/gal060
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Extracellular matrix of the human cyclic corpus luteum
1Department of Obstetrics and Gynaecology, Research Centre for Reproductive Health, University of Adelaide, Adelaide, South Australia, Australia, 2Department of Obstetrics and Gynecology, The Sahlgrenska Academy, Goteborg University, Sahlgrenska University Hospital, Goteborg, Sweden, 3Basic Medical Sciences and Clinical Developmental Sciences, St. George’s, University of London, London, UK, 4Institute for Protein Research, Osaka University, Suita, Osaka, Japan, 5Institute of Physiological Chemistry and Pathobiochemistry, Muenster University, Muenster, Germany, 6Division of Immunology, Shigei Medical Research Institute and 7Department of Molecular Biology and Biochemistry, Okayama University Medical School, Okayama, Japan
8 To whom correspondence should be addressed at: Research Centre for Reproductive Health, Discipline of Obstetrics and Gynaecology, School of Paediatrics and Reproductive Health, University of Adelaide, Adelaide, South Australia 5005, Australia. E-mail: ray.rodgers{at}adelaide.edu.au
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Abstract |
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Extracellular matrix regulates many cellular processes likely to be important for development and regression of corpora lutea. Therefore, we identified the types and components of the extracellular matrix of the human corpus luteum at different stages of the menstrual cycle. Two different types of extracellular matrix were identified by electron microscopy; subendothelial basal laminas and an interstitial matrix located as aggregates at irregular intervals between the non-vascular cells. No basal laminas were associated with luteal cells. At all stages, collagen type IV
1 and laminins 5, ß2 and 
1 were localized by immunohistochemistry to subendothelial basal laminas, and collagen type IV 1 and laminins 2, 5, ß1 and ß2 localized in the interstitial matrix. Laminin 4 and ß1 chains occurred in the subendothelial basal lamina from mid-luteal stage to regression; at earlier stages, a punctate pattern of staining was observed. Therefore, human luteal subendothelial basal laminas potentially contain laminin 11 during early luteal development and, additionally, laminins 8, 9 and 10 at the mid-luteal phase. Laminin 1 and 3 chains were not detected in corpora lutea. Versican localized to the connective tissue extremities of the corpus luteum. Thus, during the formation of the human corpus luteum, remodelling of extracellular matrix does not result in basal laminas as present in the adrenal cortex or ovarian follicle. Instead, novel aggregates of interstitial matrix of collagen and laminin are deposited within the luteal parenchyma, and it remains to be seen whether this matrix is important for maintaining the luteal cell phenotype. Key words: collagen type IV/corpus luteum/extracellular matrix/laminin/versican
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Introduction |
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The temporary endocrine units within the adult ovary—follicles and corpora lutea—continually develop and regress, thus giving rise to the day-to-day variation in hormone secretion by the ovary. Their formation and regression require considerable tissue remodelling, cellular replication, specialization and death. Much effort has been expended in understanding the hormonal and growth factor regulation of these tissue and cellular events. In stark contrast, very little research has been conducted in the ovary on the roles of extracellular matrix (see reviews, Luck, 1994
; Rodgers et al., 1998b, 1999, 2000, 2003), which also plays an important role in tissue remodelling in other organs.
Extracellular matrix has many different roles (Hay, 1991) including effects on cell adhesion, cell shape, migration, division, differentiation and cell death. All these cellular processes occur during development and regression of follicles and corpora lutea. Basal laminas are specialized sheets of extracellular matrix, which underlie the epithelial and endothelial cells and separate them from adjoining stroma (see reviews, Paulsson, 1992; Timpl and Brown, 1996; Miner and Yurchenco, 2004). They can also envelop individual cells such as muscle, nerve and fat cells and hence partition cells or groups of cells from the surrounding tissue. Basal laminas have been shown to influence epithelial cell proliferation and differentiation and orientate their polarity (Klein et al., 1988; Ekblom, 1989), and they can selectively retard the passage of soluble molecules. The basic structure of basal laminas, a collagen type IV lattice that is interconnected with a second network, is composed of laminins by the heparan sulphate proteoglycans and nidogens. Importantly, basal laminas in tissues differ in their ratios of these four major basal lamina components. Furthermore, each such ‘component’ often represents a family of different isoforms. For example, each molecule of collagen type IV comprises three chains. However, there are six different chains of collagen type IV (1–6, each encoded by a separate gene) (Hay, 1991). Because only three of these chains are required to make one collagen molecule, very many potential combinations of collagen type IV exist (e.g. 112 and 345), and each can be regarded as unique (Sado et al., 1995). Similarly, each laminin molecule is composed of three chains: one , one ß and one chain. There are five different chains, three ß chains and three chains (all encoded by separate genes and some with alternative splicing), giving rise to up to 15 identified isoforms (Miner and Yurchenco, 2004; Yurchenco et al., 2004). Thus, much complexity in the composition of basal laminas can be generated just by the different types of laminin and collagen type IV. It is now recognized that the unique composition of each basal lamina contributes to its specific functional properties.
In the ovary, the study of extracellular matrix has focused predominantly on follicles. Different types of extracellular matrix and different classes of molecules have been identified (reviewed Luck, 1994; Rodgers et al., 1998b, 1999, 2000, 2003). The follicular basal lamina, which underlies the membrana granulosa, changes considerably during follicle growth. In bovine, it commences at the primordial stage with expression of all the six collagen type IV genes, then during growth, it loses the collagen type IV 1–4 chains, acquires nidogen 1 and perlecan and increases the expression of laminins 1, ß2 and 1, the components of the laminin 3 isoform. Upon approaching a pre-ovulatory, size focimatrix develops within the membrana granulosa. Focimatrix is a novel, recently described, extracellular matrix appearing as aggregates of basal lamina-like material between granulosa cells and composed of the same components as the follicular basal lamina at the time it is produced (Irving-Rodgers et al., 2004). The other follicular layers also contain extracellular matrix. In the theca layers, the vasculature (endothelial and vascular smooth muscle) has its own associated basal laminas, and there is a generalized matrix in the theca interna referred to as the ‘thecal matrix’ (Rodgers et al., 1998a) composed of collagen type IV 1 and 2 and a laminin isoform containing the laminin 1 chain. The origins or roles of the thecal matrix, if any, are not understood. In addition, the specialized extracellular matrix of the cumulus–oocyte complex is complex and dynamic.
At ovulation, the follicular basal lamina is degraded, and the epithelial nature of the membrana granulosa is lost, as the granulosa cells luteinize into granulosa lutein cells (large luteal cells) by enlarging considerably and increasing their capacity for progesterone synthesis. The process of luteinization is considered to be an epithelial–mesenchymal transition (Rodgers et al., 2001; Rodgers and Irving Rodgers, 2002). As the follicular fluid is released at ovulation, the follicle wall folds in on itself, and the inward protrusions from the theca layers are later represented in the mature corpus luteum by septa rich in larger blood vessels and connective tissue. Cells from the theca migrate into the area of the membrana granulosa. These include connective tissue elements and endothelial cells to vascularize the corpus luteum. Cells from the theca develop into a distinct population of small steroidogenic luteal cells. In ruminants, these are considerably interspersed between the granulosa-derived large luteal cells, but in humans, they more or less retain their location at the periphery of the corpus luteum (Adams and Hertig, 1969; O’Shea et al., 1989).
In view of the extensive tissue remodelling events that occur in the transition of the follicle into a corpus luteum and during regression of a corpus luteum, changes in the extracellular matrix are to be expected. However, to date, little or no information is available, and only the bovine corpus luteum has been recently examined (Irving-Rodgers et al., 2004). Here, we examine the extracellular matrix and its composition in the human corpus luteum during its formation through regression in the menstrual cycle. Note that a new nomenclature of laminins has been proposed (Aumailley et al., 2005). We use the traditional terminology here. Laminin 8 is now laminin 411, laminin 9 is now 421, laminin 10 is now laminin 511 and laminin 11 is now laminin 521.
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Tissues
Tissues used for immunolocalization studies were from women undergoing elective surgery at the Department of Gynecology at Sahlgrenska University Hospital, Goteborg, Sweden, for non-ovarian benign gynaecological conditions. All tissue was obtained from volunteers, and informed written consent was obtained in all cases. The study was approved by the ethical committee at Goteborg University, Sweden. Histories of the last three menstrual cycles were obtained, and only women with cycle lengths between 26 and 32 days were included. All women were free of any medication for the 3 months before surgery. At surgery, the corpus luteum was excised from the ovary in total as soon as possible. The morphology of the corpus luteum subsequently confirmed the stage within the ovarian cycle of the corpora lutea. The stages and number of corpora lutea examined in this study were early (0–4 days after ovulation, n = 3), mid (5–9 days after ovulation, n = 5), late (10–15 days after ovulation, n = 6) and regressing (excised during the follicular phase, n = 1).
Corpora lutea for light and electron microscopic analysis (n = 8) were collected from women undergoing elective hysterectomy and oophorectomy at the Queen Elizabeth Hospital, Adelaide, or the Royal Adelaide Hospital for conditions including fibrosis, dermoid or ovarian cysts and endometriosis. Human placentas for use as a positive control were obtained from women undergoing elective Caesarean section at the Women’s and Children’s Hospital, Adelaide, South Australia. Signed informed consent was obtained from each patient, and ethical approval was obtained from each of the relevant ethics committee in each hospital.
Light and electron microscopy
Tissues were fixed in 2% glutaraldehyde. Following several rinses with buffer to remove excess fixative, specimens were postfixed in 2% (v/v) aqueous osmium tetroxide for 1 h at 4°C, rinsed three times with distilled water (5 min each) and then dehydrated by successive washes on ice with acetone of increasing concentration to 100%. Following overnight infiltration with epoxy resin at room temperature, specimens were embedded in fresh resin and cured at 60°C overnight. For light microscopic examination, 1-µm thick epoxy sections were stained with 1% aqueous methylene.
Immunohistochemistry
Table I has a brief summary of the antibodies used for immunohistochemistry and the fixation conditions of the tissue for each antibody. Portions of corpora lutea embedded in optimal cutting temperature (OCT) compound (Sakura Finetechnical Co., Tokyo, Japan) were used for localization using an indirect immunofluorescence method. Methods for immunohistochemistry have been reported previously (Irving-Rodgers et al., 2002). Tissue sections (10 µm) were cut from each of the frozen ovaries using a CM1800 Leica cryostat (Adeal, Altona North, Victoria, Australia), collected on glass slides treated with 0.01% poly-L-ornithine hydrobromide (catalogue no. P-4638; Sigma Chemical Co., St. Louis, MO, USA) and stored at –20°C until used.
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Sections were dried under vacuum for 5 min, followed either by fixation in 100% acetone, 100% ethanol or left unfixed. Following fixation, sections were then rinsed in 3 x 5 min changes of hypertonic phosphate–buffered saline (10 mM sodium/potassium phosphate with 0.274 M NaCl, 5 mM KCl; pH 7.2) before treatment with blocking solution [10% normal donkey serum (catalogue no. D–9663; Sigma Chemical Co.) in antibody diluent containing 0.55 M sodium chloride and 10 mM sodium phosphate (pH 7.1)] for 20 min at room temperature. Incubation with primary antibodies was carried out overnight at room temperature. For localization of molecules individually, the secondary antibodies used were biotin-SP-conjugated AffiniPure donkey anti-mouse immunoglobulin G (IgG) (1:100; catalogue no. 715-066-151), biotin-SP-conjugated AffiniPure donkey anti-rat IgG (1:100; catalogue no. 712-066-153) and biotin-SP-conjugated AffiniPure donkey anti–rabbit IgG (1:200; catalogue no. 711–066–152), followed by Cy3–conjugated streptavidin (1:100; catalogue no. 016–160–084), all from Jackson ImmunoResearch Laboratories (West Grove, PA, USA). For dual localization with PECAM–1, sections were fixed in 100% acetone, and secondary antibodies used were biotin–SP–conjugated AffiniPure donkey anti–goat IgG (1:100; catalogue no. 712–066–147), followed by fluorescein isothiocyanate (FITC)–conjugated streptavidin (1:100; catalogue no. 016–090–084) in combination with Cy3–conjugated AffiniPure donkey anti–mouse IgG (1:100; catalogue no. 715–166–151) (laminins 5 and ß1) or AffiniPure donkey anti–rat IgG (1:100; catalogue no. 712–165–153) (collagen type IV 1). Sections were mounted in mounting medium for fluorescence (catalogue no. S3023; Dako, Carpinteria, CA, USA). Controls without primary antibodies were conducted in each batch of immunostaining. No staining was observed with these controls. The validity of the staining was also supported by many different mouse or rabbit antibodies used in this study, each producing unique staining patterns.
Light and fluorescence microscopy
Sections of bovine ovary stained with methylene blue were examined using an Olympus BX50 microscope and Olympus DP12 digital camera (Olympus Australia, Mount Waverly, Australia). Sections processed for immunofluorescence staining were observed and photographed with an Olympus BX50 microscope with epifluorescence attachment and either Olympus DP12 digital camera or Spot RT digital camera (Diagnostic Instruments, Sterling Heights, MI, USA).
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At the light microscope level, luteal cells and capillaries were evident, with fewer capillaries occurring in regressing corpora lutea (Figure 1). At the electron microscope level, several previously reported features of human corpora lutea (Lunn et al., 2002
) were observed. Basal lamina underlying capillaries were observed throughout the corpus luteum (Figure 1), but there was no continuous basal lamina around individual luteal cells or around groups of luteal cells. However, occasionally, areas between luteal cells contained electron-dense extracellular matrix as illustrated in Figure 1D. These accumulations of matrix were irregularly distributed throughout the corpus luteum. The amount, location and frequency of occurrence of this matrix indicate that it is likely to be what we refer to below as interstitial matrix.
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By immunostaining for von Willibrand factor, capillaries were clearly visible in corpora lutea at all stages of development (Figure 2). Immunostaining patterns of extracellular matrix molecules similar to that of von Willibrand factor were interpretable as representing the subendothelial basal laminas. In addition, punctate patterns of immunostaining were observed with some antibodies, which were interpreted as the luteal interstitial matrix observed above at the electron microscope level. Positive immunostaining for laminins and collagen type IV occurred in this extracellular matrix and, hence, would be predicted to be ultrastructurally similar to interstitial extracellular matrix illustrated in Figure 1D.
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A summary of the staining patterns of laminins is summarized in Table II. Neither laminin 1 (Figure 3A) nor laminin 3 chains (data not shown) were detected in any corpora lutea, although they were readily detected in human placenta (Figure 3B). Laminin 1 was localized exclusively in association with the vasculature (Figure 3C and D) in all the stages of corpora lutea examined. Laminin 4 was also localized in the subendothelial basal lamina but only in the mid and late stages and in regressing corpora lutea (Figure 4B). In early corpora lutea, punctate immunostaining for laminin 4 was observed throughout the luteal parenchyma (Figure 4A). Immunostaining for laminin ß1 was similar to that of laminin 4 at all stages of corpus luteum development, but in addition, laminin ß1 was localized to the interstitial matrix at all stages (Figure 4D–F). Laminin 5 (Figure 5A–D) and ß2 chains (Figure 5E and F) localized to both the subendothelial basal lamina and the interstitial matrix at all the stages examined. Laminin 2 localized only to the interstitial matrix (Figure 5G and H) and did not change in intensity or distribution throughout development. Collagen type IV 1 was detected in the subendothelial basal lamina and in the interstitial matrix at all the stages of corpus luteum development (Figure 6A–D), with interstitial matrix staining being maximal at the mid and late stages (Figure 6B and C) as compared with the early stage (Figure 6A) and regressing corpora lutea (Figure 6D). Versican was localized to the fibrous extremities of the corpus luteum (Figure 6E and F).
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Discussion |
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We describe here the extracellular matrix composition of the human corpus luteum at different stages of development during the menstrual cycle. In general, two different types of extracellular matrix were identified using electron microscopy: subendothelial basal laminas and an interstitial matrix located as aggregates at irregular intervals between the non-vascular cells. At all stages of the corpus luteum development, collagen type IV
1 and laminins 5, ß2 and 1 were localized to subendothelial basal laminas and collagen type IV 1 and laminins 2, 5, ß1 and ß2 localized to the interstitial matrix. Laminin 4 and ß1 chains occurred in the subendothelial basal lamina only from mid-luteal to regressing stages. Laminin 1 and 3 chains were not detected in corpora lutea. Versican localized to the connective tissue capsule of the corpus luteum.
There has been speculation on the presence or absence of a basal lamina associated with luteal cells (Deane et al., 1966; Farin et al., 1986; O’Shea, 1987; Kenny et al., 1989). In an electron microscopic study of ovine corpus luteum, O’Shea et al. (1979) reported that ‘Those areas of the surface of small luteal cells which did not make close contact with neighbouring cells ... basal laminae were occasionally seen on such areas’. When referring to large luteal cells, they reported that ‘basal lamina formation on surfaces lacking cytoplasmic processes was more marked’. This would indicate that basal laminas do not completely envelope individual luteal cells in sheep. In rats, immunological electron microscopic studies identified ‘laminin specifically within perisinusoidal areas (capillaries) and in basement membrane-like plaques between lutein cells’ (Leardkamolkarn and Abrahamson, 1992). This suggests that basal laminas do not envelop or completely surround individual luteal cells of rats. Similarly, in bovine, a reticular network of fibres throughout the corpus luteum was observed by staining with antibodies to either laminin 1 or components of laminin 1 (1ß11; there was no laminin 1, 2, ß1, ß2 or collagen type IV 1, 2 or 3) (Irving-Rodgers et al., 2004). No basal lamina was observed surrounding bovine luteal cells. Light microscopic immunological studies described that laminin around luteal cells of mice (Wordinger et al., 1983) and collagen type IV (type undefined) has been localized in the human corpus luteum (Yamada et al., 1999). The pattern of immunostaining observed in the human is similar to that observed here for collagen type IV 1, wherein we claim that the staining pattern is due to the presence of collagen type IV 1 in both the subendothelial basal lamina and the interstitial matrix. Our claims are supported by electron microscopic examination and immunostaining of other matrix molecules and location of the endothelial cells by immunolocalizing von Willibrand factor and PECAM-1. Yamada et al. (1999) describe collagen type IV being ‘highly detected around both large and small luteal cells’. Whilst this is not an inaccurate statement, it fails to convey correctly that there is not a basal lamina surrounding human luteal cells.
The basal lamina components of three steroidogenic tissues have now been comprehensively described: the adrenal cortex (Virtanen et al., 2003), the ovarian follicle (Huet et al., 1997; van Wezel et al., 1998; Rodgers et al., 1998a) and now the human corpus luteum. The composition and type of extracellular matrix in these different steroidogenic tissues could be related to the different steroid hormones produced by them. In the human adrenal cortex (Virtanen et al., 2003), the glandular basal lamina contains laminin ß1 in the zona glomerulosa where aldosterone is produced, while laminin ß2 is in the zona fasciculata and zona reticularis where cortisol and androgens are produced, suggesting that the difference in extracellular matrix composition may be related to the pattern of steroidogenic hormone production in the adrenal cortex. In ovarian follicles, as they mature, they first acquire the capacity to produce androgens by their specialized stromal theca layer. Later, as the follicle enlarges approaching pre-ovulatory size, the granulosa cells acquire the capacity to produce progesterone and estradiol (E2). However, in the bovine follicle, no changes have been observed in the follicular basal lamina during the transition of these stages, even though changes in composition have been observed much earlier in follicle development (van Wezel et al., 1998; Rodgers HF et al., 1998; McArthur et al., 2000). Instead, in the days leading to ovulation, a novel extracellular matrix composed of basal lamina-like material, called focimatrix and containing laminin 1, ß2 and 1 chains, nidogen 1, perlecan and collagens type IV 1 and 2, is produced (Irving-Rodgers et al., 2004) and deposited between the cells of the multilayered membrana granulosa in the bovine. This suggests that the production of focimatrix is related to the acquisition of steroidogenic capacity by the granulosa cells. Upon formation of the corpus luteum, there is a substantial increase in the capacity to produce progesterone, but the bovine corpus luteum has no equivalent of a follicular basal lamina nor focimatrix, instead it has a reticular fibre network. Of the limited number of matrix molecules examined in the bovine, this reticular fibre network in the bovine corpus luteum contains laminin 1 but not laminins 1, 2, ß1 or ß2 or collagen type IV 1, 2 or 3 (Irving-Rodgers et al., 2004). The human corpus luteum, which also has a very high capacity to produce progesterone and additionally E2 (Sasano et al., 1989), has an interstitial matrix. It contains laminin 2, 5, ß1 and ß2 chains. It also contains collagen type IV 1. Thus, we can conclude that the different steroidogenic tissues have a variety of types of extracellular matrices and of differing composition, suggesting that they are not associated with production of any particular type of steroid hormone.
A more likely explanation for the type of matrix in steroidogenic tissues is that the matrices are related to the different cellular origins, formation and final structure of the tissues and glands themselves. The adrenal cortex has a glandular structure composed of nests of steroid-secreting cells surrounded by basal lamina, as indicated by the immunolocalization of laminins (Virtanen et al., 2003). Cells in the zona fasciculata and zona reticularis are interconnected by gap junctions (Davis et al., 2002). This is somewhat analogous to the ovarian follicle, in which the membrana granulosa cells are also connected by gap junctions (Fukushima, 1977) and surrounded by the follicular basal lamina (Rodgers et al., 2003). The corpus luteum is different in structure: the luteal cells are not epithelial but are mesenchymal or parenchymal. As shown here by immunohistochemistry and electron microscopy, there was no basal lamina around either groups or individual luteal cells but rather a diffuse and discontinuous interstitial matrix. In the human, this interstitial matrix appeared as roughly spherical aggregates that were randomly dispersed between but not associated with the vasculature. The extracellular matrix of the bovine corpus luteum has a reticular network of fibres. This difference between the human and bovine corpora lutea could be a reflection of the different level of penetration of the theca-derived luteal cells between the two species. In bovine, it is very extensive with many thecal derived cells interspersed between the granulosa-derived cells (O’Shea et al., 1989), whilst in the human corpus luteum, the degree of penetration is much less with distinct discernable theca- and granulosa-derived luteal cell layers (Adams and Hertig, 1969; Gillim et al., 1969; Lunn et al., 2002). Thus, the differences between these steroidogenic tissues could reflect the different origins of the cells and the formation and the final structure of the tissues and glands themselves.
The interstitial matrix of the human corpus luteum and the reticular fibre network of the bovine appear to be newly synthesized during the development of the corpus luteum. Upon ovulation, the follicular basal lamina is degraded allowing migration of cells into the membrana granulosa. The newly described focimatrix, at least in bovine, is also degraded (Irving-Rodgers et al., 2006), and the present study found maximal levels of the interstitial collagen type IV 1 in the mature corpora lutea. All of these observations suggest that the luteal interstitial matrix is a newly synthesized matrix of the corpus luteum and not residual focimatrix nor follicular basal lamina derived from the ovulating follicle. Additional support comes from in vitro culture of human granulosa cells where, over time, there was an increase in the levels of laminins 2, ß1 and 1 (Alexopoulos et al., 2000) and collagen type IV (type undefined) (Yamada et al., 1999). However, in these cultures, the detection of laminin 1, which we found only associated with subendothelial basal laminas may signal that these cultures also contain endothelial cells.
Laminin 4 and ß1 chains had unusual distributions in developing corpora lutea, both showing a punctate distribution in early corpora lutea and subsequent association with subendothelial basal laminas at mid-luteal stages. This is unlike laminin 2, 5 and 1 chains, which were associated with the vascular basal laminas from the early stages onwards. Therefore, human luteal subendothelial basal laminas potentially contain laminin 11 (5ß21) early during luteal development and, additionally, laminin 8 (4ß11), laminin 9 (4ß21) and laminin 10 (5ß11) when corpora lutea are fully formed by mid-luteal phase. Laminin 4 null mice are reported to have defects in neovascularization (Thyboll et al., 2002). Perhaps the distributional changes in laminin 4 reflect the neovascularization of the corpus luteum in the early stages reaching completion by the mid-luteal phase as observed previously by changes in the cross-sectional area of individual capillaries and their volume density (Suzuki et al., 1998; Gaytan et al., 1999).
The human follicle has not been extensively studied, but in the bovine follicle (van Wezel et al., 1998) and corpus luteum (Irving-Rodgers et al., 2004), only laminins 1 and 2 have been localized, but neither was detected in the subendothelial basal laminas. The subendothelial basal lamina in mature human corpora lutea contained laminins ß1 and ß2 as does the bovine corpus luteum (Irving-Rodgers et al., 2004) and the follicle (van Wezel et al., 1998), but neither has been described in regard to the vasculature in the adrenal cortex (Virtanen et al., 2003).
In ovaries, versican was originally identified in human follicular fluid aspirated from women undergoing oocyte retrieval (Eriksen et al., 1999) and in homogenates of bovine follicles (McArthur et al., 2000). Splicing produces four isoforms of versican—V0, the full-length transcript; V1, missing the GAG domain; V2, missing the GAGß domain and V3, missing both the GAG and GAGß domains (Dours-Zimmermann and Zimmermann, 1994). Using an antibody recognizing both the V0 and the V1 forms, versican was localized in both theca interna adjacent to the basal lamina and in the granulosa layers of bovine follicles (McArthur et al., 2000) but not in focimatrix (Irving-Rodgers et al., 2004). V0, V1 and V3 isoforms have been detected in mouse, rat and bovine ovaries, respectively (Russell et al., 2003a; Irving-Rodgers et al., 2006), and V2 is regarded as a brain-specific isoform (Schmalfeldt et al., 1998). At ovulation in the rat, it was recently suggested that versican produced by granulosa cells of ovulatory follicles is necessary for stabilization of the cumulus–oocyte matrix that develops in response to the LH surge (Russell et al., 2003a). Soon after, ADAMTS-1 is up-regulated in response to the LH surge, thus, proteolytically cleaving versican (Russell et al., 2003b) and initiating a rapid and continued degradation of extracellular versican as also observed in the bovine. Using an antibody recognizing all four isoforms of versican, versican was observed only at the periphery of the human corpus luteum where connective tissue elements and theca lutein cells are located. Versican isoforms have many different postulated roles, but the role of luteal versican is not known at this stage.
In summary, during the formation of the human corpus luteum, remodelling of extracellular matrix occurs producing aggregates of interstitial matrix but no basal lamina enveloping either individual or groups of luteal cells. The subendothelial basal lamina also changes composition during the formation of the corpus luteum. The structure of the extracellular matrix of the human corpus luteum is very different to that of the adrenal cortex and ovarian follicle. Whilst the extracellular matrix is dynamic in its composition and remodelled from the ovarian follicle, the precise roles played by the changing matrix have still to be identified.
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The authors thank Malgosia Krupa for assistance with immunohistochemistry. This research has been supported by the National Health and Medical Research Council of Australia, Adelaide University, The Wellcome Trust, UK, the Clive and Vera Ramaciotti Foundations and The Japan Science and Technology Agency.
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References |
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Submitted on May 11, 2006; accepted on June 6, 2006.
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