Effects of Relaxin on Neonatal Porcine Uterine Growth and Development

Abstract

Relaxin (RLX), a key reproductive hormone in pigs, stimulates uterine growth in pregnant and prepubertal gilts and in neonates 2 weeks after birth. The neonatal uterotrophic response to RLX is developmentally regulated and estrogen receptor dependent because RLX fails to increase uterine weight in the absence of estrogen receptor (ER)-alpha or when the ER is chemically inactivated. However, the role of RLX and insulin-like peptide-3 receptors, LGR7 and LGR8, respectively, in the neonatal uterotrophic response is unknown. Current studies focus on direct (LGR7/8-mediated) and indirect (ER-mediated) effects of RLX in the neonatal porcine uterus. Porcine LGR7 and LGR8 cDNAs were cloned and used as probes to identify uterine transcripts for LGR7 and LGR8, which increased from birth (postnatal day [PND] 0) to PND 14, a critical period for porcine uterine development. In situ hybridization showed that endometrial signals for both LGR7 and LGR8 are predominantly stromal during this period. Administration of RLX on PND 0, before onset of uterine ER expression, increased uterine luminal epithelial height (P < .05) but not uterine weight in the LGR7/8-positive uterus on PND 2. However, RLX increased both uterine weight and luminal epithelial height by PND 14 (P < .05), after overt endometrial ER expression. Aberrant ER activation between PND 0 and 14 alters the uterine organizational program and affects the function of adult porcine uterine tissues. Present data suggest that crosstalk between LGR7/8 and ER may be involved in estrogen-sensitive morphoregulatory events that are central to the development of an optimally functional adult uterus in the pig.

Expression of LGR7 and LGR8 by Neonatal Porcine Uterine Tissues and Transmission of Milk-Borne Relaxin into the Neonatal Circulation by Suckling

“…LGR7 and LGR8 cDNA sequences shared high homology with both mouse (82% for LGR7 and 84% for LGR8) and human (88%) sequences (27). Evidence for expression of LGR7/LGR8 in the neonatal uterus from birth through PND 14 is consistent with the fact that RLX has uterotrophic effects during this same period (4).…”

“…As an extension of work reported earlier by this laboratory (27), the objectives of this study were to determine 1) whether receptors for RLX (LGR7) and/or INSL3 (LGR8) are expressed in uterine tissues obtained at birth or on PND 7 or 14; 2) whether the temporospatial patterns of LGR7 or LGR8 uterine gene expression are affected by age or treatment with estradiol valerate (EV) during a critical period for estrogensensitive porcine uterine development between birth and PND 14; and 3) whether milk could serve as a natural exogenous source of RLX in the neonatal pig.…”

“…CA994862) and LGR8 (GenBank accession no. CA997681) cDNA sequences were found to share 88 and 85% identity with corresponding human LGR7 and LGR8 sequences and similarly high homologies with corresponding sequences at the amino acid level (27).…”

“…ISH was used to localize LGR7 and LGR8 mRNAs in uterine tissues as described previously (27). Antisense and sense [ 35 S]UTP-labeled (1000 Ci/mmol; ICN, Costa Mesa, CA) cRNA probes were produced by in vitro transcription using a MaxiScript kit (Ambion, Austin, TX).…”

Photonic Monitoring in Real Time of Vascular Endothelial Growth Factor Receptor 2 Gene Expression under Relaxin‐Induced Conditions in a Novel Murine Wound Model

“…35 Interestingly, evidence suggests that the effects of relaxin on reproductive tissue may be ER dependent 36,37 or at least involve cross-talk between relaxin receptors (LGR7/LGR8) and the ER complex. 38 Moreover, studies have highlighted the potential therapeutic role of relaxin. 39 Relaxin may be beneficial when applied at the time of wound dressing or incorporated into wound dressings and released at the site of healing to facilitate the growth and development of blood vessels and new tissue.…”