The effects of oestradiol and relaxin on extensibility and collagen organisation of the pregnant rat cervix

Cheah, Swee Hung; Ng, Kemaĭkina; Johgalingam, V T; Ragavan, Mukundan

doi:10.1677/joe.0.1460331

Cited by 18 publications

(13 citation statements)

References 16 publications

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“…Previously, we and others have shown in animal models that relaxin can alter the three-dimensional structure of collagen fibers within remodelling tissue (6,26). In our model, capsules formed around subcutaneously implanted relaxinfilled osmotic pumps were comprised of collagen fibrils that were less densely packed and frequently not in ordered parallel arrays to the same extent as they appeared in capsules formed around vehicle-loaded pumps.…”

Section: Discussionmentioning

confidence: 70%

Relaxin induces an extracellular matrix-degrading phenotype in human lung fibroblasts in vitro and inhibits lung fibrosis in a murine model in vivo.

Unemori¹,

Pickford²,

Salles³

et al. 1996

J. Clin. Invest.

323

278

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Pulmonary fibrosis is the common end stage of a number of pneumopathies. In this study, we examined the ability of the human cytokine, relaxin, to block extracellular matrix deposition by human lung fibroblasts in vitro, and to inhibit lung fibrosis in a bleomycin-induced murine model. In vitro, relaxin (1-100 ng/ml) inhibited the transforming growth factor-␤ -mediated over-expression of interstitial collagen types I and III by human lung fibroblasts by up to 45% in a dose-dependent manner. Relaxin did not affect basal levels of collagen expression in the absence of TGF-␤ -induced stimulation. Relaxin also blocked transforming growth factor-␤ -induced upregulation of fibronectin by 80% at the highest relaxin dose tested (100 ng/ml). The expression of matrix metalloproteinase-1, or procollagenase, was stimulated in a biphasic, dose-dependent manner by relaxin. In vivo, relaxin, at a steady state circulating concentration of ‫ف‬ 50 ng/ml, inhibited bleomycin-mediated alveolar thickening compared with the vehicle only control group ( P Ͻ 0.05). Relaxin also restored bleomycin-induced collagen accumulation, as measured by lung hydroxyproline content, to normal levels ( P Ͻ 0.05). In summary, relaxin induced a matrix degradative phenotype in human lung fibroblasts in vitro and inhibited bleomycin-induced fibrosis in a murine model in vivo. These data indicate that relaxin may be efficacious in the treatment of pathologies characterized by lung fibrosis. ( J. Clin. Invest. 1996. 98:2739-2745)

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Section: Discussionmentioning

confidence: 70%

Relaxin induces an extracellular matrix-degrading phenotype in human lung fibroblasts in vitro and inhibits lung fibrosis in a murine model in vivo.

Unemori¹,

Pickford²,

Salles³

et al. 1996

J. Clin. Invest.

323

278

View full text Add to dashboard Cite

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“…This finding is of interest because it indicates that the acute effects of relaxin on cervical growth and softening either require different thresholds of NO and/or are mediated by different mechanisms. Numerous studies have demonstrated that relaxin-induced softening of the rat cervix is accompanied by a reduction in the density and organization of collagen fiber bundles in the extracellular matrix (1,6,44,45), and it is generally accepted that this remodeling of collagen fibers contributes to cervical softening. Signal molecules that play key roles in relaxininduced remodeling of the cervix have not been identified.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of Nitric Oxide Synthase Activity Diminishes the Acute Effects of Relaxin on Growth, But Not Softening, of the Cervix in the Rat

Sherwood¹

2000

Endocrinology

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Relaxin promotes growth and softening of the cervix during pregnancy in the rat. This study examined the hypothesis that nitric oxide (NO) mediates the effects of relaxin on the rat cervix. To test that hypothesis, N-nitro-L-arginine methyl ester (L-NAME) was used to inhibit NO synthase, the enzyme that converts arginine to NO and L-citrulline. Nonpregnant rats were ovariectomized when they were 78 days old (day 1 of treatment). At ovariectomy each animal was fitted with silicon tubing implants containing progesterone (P) and estrogen (E) in doses that provide blood levels similar to those during late pregnancy. Rats were assigned to three treatment groups. The control group OPE (n ϭ 6 rats) received 0.5 ml L-NAME vehicle (PBS) sc at 6-h intervals from 0600 h on day 7 through 1200 h on day 8 and 0.5 ml relaxin vehicle (PBS) sc at 0600 and 1200 h on day 8. Group OPER (n ϭ 6 rats) was treated in the same way as group OPE, except that 20 g porcine relaxin were administered. Group OPERI (n ϭ 7 rats) was treated in the same way as group OPER, except that L-NAME was administered at a dose of 100 mg/kg⅐6 h. Between 1400 -1500 h on day 8, the cervices were removed and weighed. Cervical wet weight and extensibility were markedly greater (P Ͻ 0.01) in relaxintreated group OPER rats than in group OPE controls. Treatment with L-NAME diminished relaxin's effects on cervical wet weight, but not cervical extensibility. In conclusion, this study provides evidence that NO contributes to the acute effects of relaxin on the growth, but not the softening, of the rat cervix. (Endocrinology 141: 2458 -2464, 2000) R ELAXIN is produced and secreted by the corpora lutea during the second half of pregnancy in the rat (1). One vital physiological role of relaxin throughout this period is to promote the progressive and marked growth and softening of the cervix that is required for rapid and safe delivery (2-5). Studies at the light microscope level demonstrated that relaxin increases the accumulation of new epithelial and stromal cells (6, 7), reduces the organization and density of collagen fiber bundles (6), reduces the length of elastin fibers (6), and increases the cross-sectional area of arteries (6).The molecular mechanisms that mediate the effects of relaxin in the cervix are poorly understood. The free radical molecule nitric oxide (NO) is known to play a key role in the regulation of mammalian physiology through its effects in cardiovascular, nervous, renal and other systems (8 -10). NO is produced from one of the two guanidino moieties of the amino acid l-arginine in a reaction catalyzed by the oxidoreductase enzyme NO synthase (NOS) with l-citrulline as coproduct. There are three isoforms of NOS: the so-called constitutive isoforms, endothelial NOS (eNOS or NOS-III) and neuronal NOS (nNOS or NOS-I), and inducible NOS (iNOS or NOS-II). All three NOS isoforms are expressed in the rat cervix during pregnancy (11, 12). There are reasons to suspect that the effects of relaxin on the rat cervix are mediated at least in part...

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“…Oestrogen becomes the dominant hormone at parturition in the ewe, when it induces cervical ripening (Ellwood 1980, Winn et al 1994, Cheah et al 1995, Silva et al 1995 and the formation of myometrial gap junctions (Garfield et al 1980, Ciray et al 1996. Although the Figure 4 The expression of oestradiol receptor (E2R) mRNA in the maternal caruncles or villi was localised by in situ hybridisation.…”

Section: Discussionmentioning

confidence: 99%

Regulation of oxytocin receptor in the placentome capsule throughout pregnancy in the ewe: the possible role of oestradiol receptor, progesterone receptor and aromatase

Leung

Reynolds²,

Wathes³

1998

Journal of Endocrinology

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The hormonal regulation of uterine oxytocin receptors (OTR) during the establishment of pregnancy and at parturition has been studied extensively, but little information is available during mid-pregnancy. This study investigated the localisation of OTR mRNA in the ovine placentome throughout gestation and related this to expression patterns for the putative regulatory agents aromatase, oestradiol receptor, progesterone receptor and oxytocin. Placentomes were collected at regular intervals throughout pregnancy for in situ hybridisation analysis and immunocytochemistry (oestradiol receptor only). Results were quantified by optical density measurements of autoradiographs. Progesterone receptor mRNA was localised to the caruncular tissues on day 30 but became undetectable by day 34. Aromatase mRNA appeared in the fetal villi at days 34-40, with concentrations peaking at days 52-55 and again at days 132-137. Oestradiol receptor mRNA was localised to the caruncular tissues from days 13 to 30 and found in the maternal villi and placentome capsule from days 45 to 70. Oestradiol receptor protein was barely detectable in either tissue. OTR mRNA was localised to the placentome capsule at days 34-40, remaining high at day 45 and declining to basal levels by days 132-137. Oxytocin mRNA was not detected in the placentome. In conclusion: (1) progesterone acting via its receptor may suppress the expression of aromatase and OTR in early pregnancy; (2) the up-regulation of OTR expression in the capsule may not involve the oestradiol receptor; (3) there is a differential regulation between different regions of the uterus as the increase in the placentome capsule occurs at a time when concentrations in the rest of the endometrium and myometrium remain low; (4) oestradiol receptor expression in the placentome may be regulated at the translational level; and (5) there is no local production of oxytocin in the sheep placenta. The role of OTRs in the capsule during mid-pregnancy remains to be determined.

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The effects of oestradiol and relaxin on extensibility and collagen organisation of the pregnant rat cervix

Cited by 18 publications

References 16 publications

Relaxin induces an extracellular matrix-degrading phenotype in human lung fibroblasts in vitro and inhibits lung fibrosis in a murine model in vivo.

Relaxin induces an extracellular matrix-degrading phenotype in human lung fibroblasts in vitro and inhibits lung fibrosis in a murine model in vivo.

Inhibition of Nitric Oxide Synthase Activity Diminishes the Acute Effects of Relaxin on Growth, But Not Softening, of the Cervix in the Rat

Regulation of oxytocin receptor in the placentome capsule throughout pregnancy in the ewe: the possible role of oestradiol receptor, progesterone receptor and aromatase

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