Role of Relaxin and Estrogen in the Control of Eosinophilic Invasion and Collagen Remodeling in Rat Cervical Tissue at Term1

Luque, Enrique H.; Toro, Mónica Muñoz de; Ramos, Jorge G.; Rodríguez, Horacio Adolfo; Sherwood, O. D.

doi:10.1095/biolreprod59.4.795

Cited by 57 publications

(46 citation statements)

References 40 publications

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“…These increases in macrophage numbers correlated with increased OD, an indication of decreased collagen structure (i.e., reduced birefringence reflecting collagen fibers that are fragmented, loosely packed, and dilated). The time course of cervical restructuring as pregnancy neared normal term in wildtype controls was directly comparable to that in Ptgfr À/À mice that did not progress to birth, as well as that previously reported for remodeling of the prepartum cervix in C3H/HeN mice [35,41] and in the pregnant rat [27,44]. With evidence that birefringence was reduced due to collagen disarray and…”

Section: Discussionsupporting

confidence: 85%

Parturition and Recruitment of Macrophages in Cervix of Mice Lacking the Prostaglandin F Receptor1

Yellon

Ebner

Sugimoto

2008

Biology of Reproduction

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Section: Discussionsupporting

confidence: 85%

Parturition and Recruitment of Macrophages in Cervix of Mice Lacking the Prostaglandin F Receptor1

Yellon

Ebner

Sugimoto

2008

Biology of Reproduction

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“…Although the current study is the first to demonstrate stimulatory migration effects of relaxin in mononuclear leukocytes, a number of studies have reported inhibitory functions for relaxin through a nitric oxide-dependent pathway in mast cells (30), platelets (32), and the polymorphonuclear leukocytes neutrophils (37) and basophils (38). Although relaxin has no effect on polymorphonuclear eosinophil invasion of the rat cervix during pregnancy (73), other studies have reported that relaxin positively regulates the migratory capacity of epithelial cells. Relaxin can stimulate migration and invasion of human breast cancer cells MCF-7 and SK-BR3 on matrigel-coated transwells (8).…”

Section: Discussionmentioning

confidence: 64%

Relaxin Stimulates Leukocyte Adhesion and Migration through a Relaxin Receptor LGR7-dependent Mechanism

Figueiredo

Mui

Nelson

et al. 2006

Journal of Biological Chemistry

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Leukocytes are critical effectors of inflammation and tumor biology. Chemokine-like factors produced by such inflammatory sites are key mediators of tumor growth that activate leukocytic recruitment and tumor infiltration and suppress immune surveillance. Here we report that the endocrine peptide hormone, relaxin, is a regulator of leukocyte biology with properties important in recruitment to sites of inflammation. This study uses the human monocytic cell line THP-1 and normal human peripheral blood mononuclear cells to define a novel role for relaxin in regulation of leukocyte adhesion and migration. Our studies indicate that relaxin promotes adenylate cyclase activation, substrate adhesion, and migratory capacity of mononuclear leukocytes through a relaxin receptor LGR7-dependent mechanism. Relaxin-stimulated cAMP accumulation was observed to occur primarily in non-adherent cells. Relaxin stimulation results in increased substrate adhesion and increased migratory activity of leukocytes. In addition, relaxinstimulated substrate adhesion resulted in enhanced chemotaxis to monocyte chemoattractant protein-1. These responses in THP-1 and peripheral blood mononuclear cells are relaxin dose-dependent and proportional to cAMP accumulation. We further demonstrate that LGR7 is critical for mediating these biological responses by use of RNA interference lentiviral short hairpin constructs. In summary, we provide evidence that relaxin is a novel leukocyte stimulatory agent with properties affecting adhesion and chemomigration.Complex interactions between tumor cells and the immune system regulate disease progression by stimulating cell proliferation, neovascularization, tissue remodeling, and metastasis or by inhibiting the host anti-tumor immune response (1). However, the factors produced by tumor cells that affect their immune surveillance remain to be fully elucidated. The insulin-related peptide hormone, relaxin, possesses key features required of a tumor-derived factor capable of affecting malignant progression, and its emerging role as a putative mediator of tumor progression has been recently reviewed (2). In humans, relaxin is encoded by three genes designated H1, H2, and H3 (3). Functionally, relaxin is classically described to improve blood supply to multiple organs including the uterus, mammary gland, lung, and heart (4). Relaxin is also known to increase matrix metalloproteinase expression, resulting in collagen turnover of reproductive tissues and in models of fibrosis, and is responsible for lengthening of the interpubic ligament during delivery (3-5).A role for relaxin in cancer progression was first suggested 38 years ago by studies indicating that carcinogen-fed rats experienced substantially enhanced mammary tumor growth when co-treated with relaxin several weeks later (6). More recently, relaxin has been shown to support growth and invasiveness of breast cancer cells (7,8), and elevated relaxin serum levels are positively correlated with breast cancer metastases (9). Relaxin immunostaining has been dem...

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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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Role of Relaxin and Estrogen in the Control of Eosinophilic Invasion and Collagen Remodeling in Rat Cervical Tissue at Term1

Cited by 57 publications

References 40 publications

Parturition and Recruitment of Macrophages in Cervix of Mice Lacking the Prostaglandin F Receptor1

Parturition and Recruitment of Macrophages in Cervix of Mice Lacking the Prostaglandin F Receptor1

Relaxin Stimulates Leukocyte Adhesion and Migration through a Relaxin Receptor LGR7-dependent Mechanism

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

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