The effect of relaxin on the endometrium of monkeys histological and histochemical studies

Dallenbach-Hellweg, Gisela; Dawson, Alden B.; Hisaw, Frederick L.

doi:10.1002/aja.1001190105

Cited by 57 publications

(30 citation statements)

References 33 publications

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“…The results of these earlier studies, also in the rhesus monkey, suggested that relaxin induces proliferation of endothelial cells of endometrial blood vessels and dilatation of superficial endometrial blood vessels (33). Animals in which administration of relaxin-containing extracts was discontinued but steroid treatment was maintained showed reduced endothelial proliferation and dilatation (32). Thus, relaxin seemed necessary to maintain endothelial proliferation and vascular dilatation in the endometrium of the rhesus monkey.…”

Section: Discussionmentioning

confidence: 73%

“…Uterine weight, P ϭ 0.014. bition of MMP expression, allowing maintenance of connective tissue integrity, provides evidence for relaxin's important role in endometrial support. Hisaw and coworkers (32,33) performed the first studies to suggest that relaxin affects endometrial vascularization. The results of these earlier studies, also in the rhesus monkey, suggested that relaxin induces proliferation of endothelial cells of endometrial blood vessels and dilatation of superficial endometrial blood vessels (33).…”

Section: Discussionmentioning

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: Discussionmentioning

confidence: 73%

Section: Discussionmentioning

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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“…The first evidence suggesting that RLX affects the vasculature was based on histological studies conducted in the uterus. In 1966, Dallenbach-Hellweg and colleagues (18) described an enlargement of arterioles and capillaries in the superficial portions of the endometrium of castrated monkeys treated with RLX (18). In a later study also in monkeys, they reported not only an enlargement of the vessels but also endothelial cell proliferation in the endometrial vessels (48).…”

Section: Influence Of Rlx On the Vasculature Of Other Organsmentioning

confidence: 89%

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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“…Uterotrophic actions of relaxin, first described in the rat (Steinetz et al 1957), include both uterine water imbibition (Steinetz et al 1957, Zarrow & Brennan 1957 and increased uterine dry matter content associated with protein, collagen and glycogen accretion (Steinetz et al 1957, Vasilenko et al 1980, 1981, Vasilenko & Mead 1987. Early studies indicating that relaxin-rich extracts promoted endometrial growth in juvenile and ovariectomized rhesus monkeys (Hisaw & Hisaw 1964, Dallenbach-Hellweg & Hisaw 1966 were later confirmed by work involving the purified hormone (Goldsmith et al 2004), which showed that relaxin also stimulated endometrial angiogenesis. Consistently, relaxin administered in the peri-implantation period increased endometrial thickness in the macaque (Hayes et al 2004).…”

Section: Introductionmentioning

confidence: 99%

Uterotrophic effects of relaxin related to age and estrogen receptor activation in neonatal pigs

Yan

Ryan²,

Bartol³

et al. 2006

Reproduction

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While uterotrophic effects of relaxin are well documented, the mechanism through which relaxin promotes uterine growth is incompletely understood. Studies in rats suggest that relaxin-stimulated uterine edema depends on estrogen receptor (ER) activation. Here, neonatal pigs were used to investigate the interaction between relaxin and ER signaling pathways. Gilts were treated either at birth (postnatal day (PND) 0) (study 1) before the onset of endometrial ERa expression, or on PND 12 (study 2) after the onset of ERa expression. In study 1, gilts were treated with estradiol-17b or porcine relaxin for two days and uteri were collected on PND 2. In study 2, PND 12 gilts were treated with a single injection of the ER antagonist ICI 182,780 (ICI) or vehicle. Two hours later, gilts were given either estradiol-17b or porcine relaxin for two days. When administered for two days from birth (study 1), neither estradiol-17b nor relaxin affected uterine weight or protein content. However, uterine luminal epithelial height was greater in relaxin-than in vehicle-treated gilts. In contrast, in study 2, both estradiol and relaxin increased uterine weight, protein content and uterine luminal epithelial height on PND 14. These effects were inhibited by pre-treatment with ICI in both estradiol-and relaxin-treated gilts. The results indicate that uterotrophic effects of relaxin in the neonatal pig are related to age and to both the relative presence and state of activation of the ER system in developing uterine tissues between birth and PND 14.

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The effect of relaxin on the endometrium of monkeys histological and histochemical studies

Cited by 57 publications

References 33 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

Uterotrophic effects of relaxin related to age and estrogen receptor activation in neonatal pigs

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