Relaxin regulation of endometrial structure and function in the rhesus monkey

Abstract

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...

Relaxin Enhances S100A4 and Promotes Growth of Human Thyroid Carcinoma Cell Xenografts

“…Isolated HUVEC cells were reported to respond to relaxin with increased the production of nitric oxide synthase II and increased nitric oxide generation (51). Relaxin was also shown to induce vascular endothelial growth factor and procollagenase expression in human endometrial cells and to stimulate blood vessel formation in the primate endometrium (52,53). Here, we show for the first time a direct angiogenetic effect of RLN2 by promoting endothelial tube formation of HUVEC by RLN2.…”

H2 relaxin overexpression increases in vivo prostate xenograft tumor growth and angiogenesis

“…Other investigators have observed that the effect of relaxin on MMP regulation appears to be cell-type specific. For example, the upregulation, 10,28 downregulation 39,40 and biphasic regulation 27 of MMPs by relaxin have been reported before. In tumor biology, MMPs have been implicated in a variety of processes: a) the degradation of the ECM allowing for cell migration; 41 b) the alteration of the ECM microenvironment resulting in changes of cellular behaviour; 41 and c) the modulation of biologically active molecules by direct cleavage, release from bound stores or modulation of the activity of tissue inhibitors of MMPs (TIMPs).…”

Regulation of the reproductive cycle and early pregnancy by relaxin family peptides

“…However, a similar decidualisation response can also be induced by relaxin alone, acting through RXFP1, but within a much shorter time-frame of only 2-3 days . Moreover, studies using monkeys have shown that supplementary relaxin in vivo is able to specifically induce a thickening of the endometrium, improved vascularization, and reduced pregnancy loss (Goldsmith et al, 2004;Hayes et al, 2004;Einspanier et al, 2009), consistent with a very positive impact on implantation and placentation. Also in women, it has been shown that there is a good association between mid-pregnancy levels of circulating relaxin, reduced spontaneous abortion, and increased blood flow (Jauniaux et al, 1994;Anumba et al, 2009).…”

“…Goldsmith et al, 2004). It appears to achieve this by a local induction of vascular endothelial growth factor, VEGF, for example by endometrial stromal cells (Unemori et al, 1999).…”