Relaxin Stimulates Uterine Edema via Activation of Estrogen Receptors: Blockade of its Effects Using ICI 182,789, a Specific Estrogen Receptor Antagonist

Abstract

Relaxin's ability to stimulate uterine growth is well established. The mechanisms by which relaxin exerts this effect, however, remain unclear. In light of previous work demonstrating peptide growth factor activation of estrogen receptors (ERs), the present study was conducted to determine if relaxin similarly stimulates ERs. Twenty-five day-old female Sprague-Dawley rats were bilaterally ovariectomized and treated with estradiol or porcine relaxin alone or in combination with the ER antagonist ICI 182,780. Following treatment with 17beta-estradiol or relaxin alone, the uterine weight/body weight ratio (UtW/BW) increased significantly over control values (+98% and +77% respectively, p<0.0003). Pre-treatment of animals with ICI 182,780 (3 microg/g BW) prior to either estradiol or relaxin treatment completely inhibited the hormone-induced increases in uterine weight (p<0.0005). ICI 182,780 alone had no significant effect. Histological analysis of uterine cross-sections revealed that the edema present in the endometrium of animals treated with estradiol or relaxin alone was completely absent in the uteri of animals pre-treated with ICI 182,780. These data indicate that relaxin-induced uterine edema and growth is mediated by ERs.

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

“…Collectively, these studies suggest that the age-specific, uterotrophic effects of relaxin are developmentally regulated and that the effects of relaxin in this system are dependent, in part, on ER activation. These findings agree with research in rats, involving a similar experimental approach with ICI 182,780, in which relaxin-stimulated uterine edema was interpreted to be ER-dependent (Pillai et al 1999).…”

“…every 6 h for 48 h; n ¼ 6); and (6) ICI/relaxin (n ¼ 10). Timing, dosage and route of ICI administration were based on studies in rodents (Gibson et al 1991, Pillai et al 1999, while those for relaxin administration were based on studies in prepubertal gilts and rodents (Hall et al 1990, Pillai et al 1999. In both studies, gilts were weighed and killed 3 h after the last injection on either PND 2 (study 1) or PND 14 (study 2).…”

“…Crosstalk involving estrogen-independent, growth factor-dependent estrogen receptor (ER) activation is well documented (Smith 1998). Data indicating that pretreatment of ovariectomized rats with the ER antagonist ICI 182,780 inhibited relaxin-induced uterine edema were interpreted to indicate that relaxin could be acting, in part, through crosstalk with the ER system (Pillai et al 1999). Similar effects have not been documented in other species.…”

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

“…This anti-hypertrophic effect could be a self-protective action of the cervix in relation to the actual endocrine milieu, and is consistent with the anti-hypertrophic effects of RLX in cultured neonatal rat cardiomyocytes (Moore et al 2007). In another organ, the rat cervix, a supportive interaction between RLX and E2 has been described, where RLX is a ligand-independent activator of ERs inducing edema and uterine growth (Pillai et al 1999). However, this action of RLX could not be confirmed in our study, again supporting RLX's difference among species and organs.…”

Relaxin (RLX) and estrogen affect estrogen receptor α, vascular endothelial growth factor, and RLX receptor expression in the neonatal porcine uterus and cervix

“…Growth of the female reproductive tract (FRT) is sensitive to both estrogen and relaxin (RLX;Vasilenko & Mead 1987, Cullinan-Bove & Koos 1993, Hall & Anthony 1993, Pillai et al 1999, and organizational events responsible for both tissue patterning and programming are estrogen receptor (ER) dependent (Couse & Korach 1999, Tarleton et al 1999. Thus, factors that affect ER expression and activation can determine the developmental trajectory of these tissues (Schonfelder et al 2002, Suzuki et al 2002, Nikaido et al 2005.…”