Relaxin Positively Regulates Matrix Metalloproteinase Expression in Human Lower Uterine Segment Fibroblasts Using a Tyrosine Kinase Signaling Pathway

Palejwala, Smita; Stein, Daniel E.; Weiss, Gerson; Monia, Brett P.; Tortoriello, Drew V.; Goldsmith, Laura T.

doi:10.1210/endo.142.8.8295

Cited by 96 publications

(58 citation statements)

References 45 publications

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“…** Western Blot Analyses. Western blot analyses employing specific, well characterized primary antibodies and semiquantitative methods described previously (29,30) were used to determine expression of the steroid hormone receptors, MMPs, and TIMP-1. Mouse monoclonal antibodies to human procollagenase (proMMP-1) (Ab-1), human prostromelysin (proMMP-3) (Ab-1), and human TIMP-1 (Ab-1), human estrogen receptor ␣ (GR17), human estrogen receptor ␤ (GR39), pure proMMP-1, proMMP-3, and TIMP-1 proteins and peroxidase-conjugated goat anti-mouse IgG and IgM were from Calbiochem͞Oncogene Research Products.…”

Section: Methodsmentioning

confidence: 99%

“…Subsequently, the blots were washed three times with Tris-buffered saline Tween 20 over a 30-min period and developed by the enhanced chemiluminescence method. Intensities of the signals obtained on developed films were determined with a computing densitometer (model 300B, Molecular Dynamics) by using the volume-integration method with appropriate corrections for background absorption, as we have described previously (29,30). Samples from all monkeys were run on the same blot.…”

Section: Methodsmentioning

confidence: 99%

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Relaxin regulation of endometrial structure and function in the rhesus monkey

Goldsmith

Weiss

Palejwala

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

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Despite the documented importance of the protein hormone relaxin in reproduction in various mammalian species, the role of relaxin in human reproduction is poorly understood, largely because of the lack of studies in women or in suitable non-human primate models. Here we describe the establishment of a nonhuman primate model of early human pregnancy and its use in defining the actions of relaxin. Results demonstrate that relaxin exerts dramatic uterine effects including pronounced increase in uterine weight and stimulation of endometrial angiogenesis and resident endometrial lymphocyte number. In addition, relaxin decreases endometrial levels of matrix metalloproteinases 1 and 3 and increases levels of their endogenous inhibitor, tissue inhibitor of metalloproteinase 1, resulting in maintenance of endometrial collagen content. Relaxin significantly inhibits endometrial levels of estrogen receptor ␣, but not ␤, and of progesterone receptor isoforms A and B. The findings that relaxin stimulates new blood vessel formation and increases cytokine-containing lymphocyte number while maintaining endometrial connective tissue integrity are consistent with a significant role of relaxin in the establishment and͞or maintenance of early pregnancy.R elaxin is a 6-kDa protein hormone member of the insulinlike growth factor family present in circulation in women during the latter part of the menstrual cycle and throughout pregnancy (1). In many mammalian species, relaxin exerts pronounced effects on the female reproductive tract that are involved in the maintenance of pregnancy and successful parturition (2, 3). Relaxin is important for normal delivery in several mammalian species because of its marked rearrangement of reproductive tract connective tissue (2-4). Despite the documented importance of relaxin in various mammalian species, the role of relaxin in human reproduction is, to date, an important, yet unanswered, question. Elucidation of the role of relaxin in women has been hampered by the inability to perform studies in women and by the lack of studies performed in suitable primate models of human pregnancy. Here we describe the establishment of a non-human primate model of early human pregnancy and its use in defining the actions of relaxin. Results demonstrate that relaxin exerts dramatic uterine effects including pronounced increase in uterine weight, stimulation of endometrial angiogenesis and resident lymphocyte number, maintenance of endometrial connective tissue integrity, and inhibition of endometrial estrogen and progesterone action. These effects are the developmental changes that occur in the human uterus during the late secretory phase of the menstrual cycle and early pregnancy. These findings support the thesis that relaxin acts as an important factor in uterine accommodation to and maintenance of early pregnancy in women.The dramatic species differences in the sources, secretion patterns, and target organs of relaxin have contributed greatly to the lack of understanding of the role of relaxin in human repr...

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Relaxin regulation of endometrial structure and function in the rhesus monkey

Goldsmith

Weiss

Palejwala

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

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“…1. One possibility to be discussed in detail here is based on the confluence of several observations: 1) the crucial role for RLX, the endothelial ET B receptor, and NO in pregnancy-mediated renal vasodilation as described above, 2) the ability of RLX to upregulate matrix metalloproteinase activity (MMP) activity (at least in fibroblasts; 82,105,108), and 3) the potential for vascular MMPs, such as MMP-2, to process big ET at the Gly-Leu bond to yield ET , the latter capable of activating ET receptors (31,32). Thus RLX may upregulate MMP-2 activity in the renal vasculature during pregnancy, thereby leading to renal vasodilation, hyperfiltration, and reduced myogenic reactivity of small renal arteries in an ET-and NO-dependent fashion.…”

Section: And Citations Therein)mentioning

confidence: 99%

Emerging role of relaxin in renal and cardiovascular function

Conrad

Novak

2004

American Journal of Physiology-Regulatory, Integrative and Comp

133

113

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Conrad, Kirk P., and Jacqueline Novak. Emerging role of relaxin in renal and cardiovascular function. Am J Physiol Regul Integr Comp Physiol 287: R250 -R261, 2004; 10.1152/ajpregu.00672.2003.-Although traditionally associated with reproductive processes, relaxin is emerging as an important player in renal and cardiovascular function. Much of our recently acquired understanding of relaxin in this new context has arisen from studies of maternal renal and cardiovascular adaptations to pregnancy in rats where the hormone is turning out to be an important mediator. First, we highlight the influence of relaxin on renal hemodynamics and glomerular filtration rate, as well as on other peripheral circulations. Second, we discuss the effect of relaxin on both the steady and pulsatile systemic arterial load, as well as on the heart, in particular, coronary blood flow. Third, we consider the impact of the hormone on cultured endothelial and vascular smooth muscle cells. Fourth, we address the interaction of relaxin with renal and cardiac disease, as well as its role in angiogenesis. Finally, in Perspectives, we point out several key research questions in need of investigation that relate to a potential autocrine/paracrine role of relaxin in renal and cardiovascular tissues. Furthermore, on the basis of its potent vasodilatory and matrix-degrading attributes, we speculate about the therapeutic potential of relaxin in renal and cardiovascular diseases. pregnancy; kidney circulation; glomerular filtration; osmoregulation; peripheral circulation; systemic hemodynamics; vasodilation; arterial compliance; heart; myogenic reactivity; angiogenesis; relaxin receptors; matrix metalloproteinase; gelatinase; endothelin B receptor; nitric oxide; angiotensin II THE OBJECTIVE OF THIS REVIEW is to highlight the new and emerging roles of relaxin (RLX) in the renal and cardiovascular systems. Traditionally, RLX has been tied to reproductive processes during pregnancy, because most investigations conducted by reproductive biologists have dealt with the hormone in this context. The traditional sources of RLX have been reproductive tissues such as the corpus luteum of the ovary from which the hormone emanates and circulates during the luteal phase of the menstrual cycle and during pregnancy in women (95). Furthermore, there has been no well-established role in the male. However, the concept of a role for RLX in cardiovascular function actually has its antecedents early on in the history of RLX research, when Frederick L. Hisaw, who discovered the hormone (47, 113), noted that after administration of RLX to castrated monkeys, there were marked morphological changes in the endothelial cells of the endometrium consistent with hypertrophy and hyperplasia (48). The concept that RLX can affect blood vessel structure and function has since gained considerable support, particularly in the last decade. Much of our recently gained knowledge of RLX in this new light has arisen from studies of maternal renal and cardiovascular function in the gravid rat mo...

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“…This would also explain the fast widening action of locally applied RLX on the marmoset cervix obtained in our study, while RLX has been shown to stimulate a number of intracellular pathways, including those involved with NO synthase II (Samuel et al 2007a(Samuel et al , 2007b. Therefore, RLX seems to act differently on cervical ripening: a mediator of collagen turnover by stimulating the breakdown of collagen through MMP stimulation (Palejwala et al 2001 In all hormonal treated groups, a decline (not significant) in cervical collagen content was detected by histological and biochemical means. This reduction of collagen was due to different mechanisms, involving an increased local MMP release, number of eosinophil cells and RLX responsibility of the cervical tissue by increasing RXFP1 expression.…”

Section: Discussionmentioning

confidence: 85%

The hormonal induction of cervical remodeling in the common marmoset monkey (Callithrix jacchus)

Simon¹,

Einspanier

2009

Reproduction

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Controversy still exists regarding the involvement of relaxin (RLX) in cervical reorganization throughout parturition in the human, despite its well-known role in facilitating extensive extracellular matrix (ECM) remodeling in diverse organs. Therefore, the aim of the present study was to examine the influence of RLX and estrogen (E2) on the cervical tissue of the common marmoset monkey. Two experimental designs were used: 1) in vivo analysis of the intracervical diameter under locally applied RLX and 2) ovariectomized (ov) marmosets were treated systemically with either recombinant human (rh) RLX, E2 or rhRLXCE2 to examine their action on the cervix. In vivo-locally applied rhRLX induced a distinct and significant widening of the cervix (before: 4.8G1.1 mm versus after: 5.7G0.9 mm in diameter; P!0.030, MVGS.E.M.). This widening effect was most pronounced in animals without previous pregnancies. In vitro investigation of cervical tissue showed significantly increased wet weights after all three hormone treatments (E2: 0.27G0.07 g, RLX: 0.25G0.04 g, E2C RLX: 0.30G0.11 g; all P!0.05; MVGS.E.M.) versus controls (0.10G0.04 g). Furthermore, morphological changes such as loosening of the connective tissue structure and decline in collagen content, an increase in the number of eosinophils, increased the expression of matrix metalloproteinases (MMP1) and MMP2, as well as gene and protein expression of the RLX receptor RXFP1 could be detected in the cervical tissue after all hormone treatments, compared with controls. In summary, RLX has a potent widening effect on the cervix of the common marmoset monkey. Although E2 is not required for this RLX effect, a combined application of E2 and RLX induced the most prominent cervical ripening.

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Relaxin Positively Regulates Matrix Metalloproteinase Expression in Human Lower Uterine Segment Fibroblasts Using a Tyrosine Kinase Signaling Pathway

Cited by 96 publications

References 45 publications

Relaxin regulation of endometrial structure and function in the rhesus monkey

Relaxin regulation of endometrial structure and function in the rhesus monkey

Emerging role of relaxin in renal and cardiovascular function

The hormonal induction of cervical remodeling in the common marmoset monkey (Callithrix jacchus)

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