Insulin-Like Growth Factor Binding Proteins -1 and -3, and Hydroxysteroid (11-Beta) Dehydrogenase One: Potential Roles in Ruminant Conceptus Development and Endometrial Function

Maternal contributions from the uterine endometrial luminal (LE) and glandular (GE) epithelia are unequivocally required to support ruminant conceptus growth and development, elongation and implantation. Therefore, studies were conducted to examine expression of endometrial genes hypothesized to regulate conceptus development. The first study investigated two genes specifically expressed in the LE and superficial GE of the ovine uterus. Insulin-like growth factor binding protein (IGFBP1) and (IGFBP3) expression was coordinate with ovine conceptus elongation. Treatment with P4 induced and IFNT stimulated IGFBP1, but not IGFBP3; however, IFNT only moderately stimulated IGFBP1, indicating that another conceptus-derived factor stimulates endometrial IGFBP1 expression. IGFBP1 did not affect proliferation of ovine trophectoderm (oTr) cells in vitro, but stimulated their migration and attachment. Results indicated that IGFBP1, but not IGFBP3 is a marker of conceptus elongation in ruminants and stimulates cell migration and attachment. The second study evaluated the effects of pregnancy, P4 and IFNT on expression of hydroxysteroid (11-beta) dehydrogenases (HSD11B1 and HSD11B2), nuclear receptor subfamily 3, group C, member 1 (NR3C1), and prostaglandin-endoperoxide synthase 2 (PTGS2) in the ovine uterus. Expression of HSD11B1 mRNA and PTGS2 protein in endometrial LE and sGE were coordinate with conceptus elongation, while HSD11B2 mRNA was expressed primarily in the conceptus. Further, P4 induced, but IFNT only moderately stimulated HSD11B1. Thus, HSD11B1 expression may be regulated by prostaglandins (PGs) during early pregnancy. The presence of NR3C1 in the ovine uterus implicates cortisol, the main product of HSD11B1, in peri-implantation period events that include elongation of the ovine conceptus. The third study determined in vivo effects of PGs on ovine conceptus elongation and endometrial gene expression. Compared to control ewes, intrauterine infusions of a PTGS2 inhibitor, meloxicam, retarded elongation and decreased expression of elongation-related genes including IGFBP1, IGFBP3, HSD11B1, galectin 15 (LGALS15), solute carrier family 2, member 1 (SLC2A1), gastrin-releasing peptide (GRP), cystatin C (CST3), radical S-adenosyl methionine domain containing 2 (RSAD2), and ISG15 ubiquitin-like modifer (ISG15). Collectively, these studies assessed the effects of pregnancy, P4, IFNT, and PGs on endometrial genes implicated in conceptus growth. These results indicate that IGFBP1 is a marker of conceptus elongation in ruminants and provide novel roles for both cortisol and PGs in endometrial gene expression and conceptus elongation.