Prostaglandin E2 functions as a luteotrophic factor in the dog

Abstract

The luteal phase in dogs is governed by many poorly understood regulatory mechanisms. Functioning of the corpus luteum (CL) is unaffected by hysterectomy. Recently, the role of prostaglandins in regulating canine CL function was addressed suggesting a luteotrophic effect of prostaglandin E 2 (PGE 2 ) during the early luteal phase. However, compelling functional evidence was lacking. The potential of PGE 2 to stimulate steroidogenesis was tested in canine primary luteal cells isolated from developing CL of non-pregnant dogs. In addition, the luteal expression of prostaglandin transporter (PGT) and steroidogenic acute regulatory protein (STAR) was demonstrated and characterized in CL from non-pregnant bitches during the course of dioestrus as well as from pregnant animals during the preimplantation, post-implantation and mid-gestation periods of pregnancy and during luteolysis; the luteal expression of PGE 2 receptors (EP2 and EP4) has been investigated at the protein level throughout pregnancy. Our findings show that PGE 2 is an activator of STAR expression in canine luteal cells from early luteal phase, significantly up-regulating STAR promoter activity and protein expression resulting in increased steroidogenesis. The 3bHSD (HSD3B2) and P450scc (CYP11A1) expression remained unaffected by PGE 2 treatment. The expression of PGT was confirmed in CL during both pregnancy and dioestrus and generally localized to the luteal cells. After initial up-regulation during the earlier stages of the CL phase, its expression declined towards the luteal regression. Together with the demonstration of EP2 and EP4 throughout pregnancy, and the decline in EP2 at prepartum, our findings further support our hypothesis that intra-luteal PGE 2 may play an important role in regulating progesterone secretion in the canine CL.

Formation of the early canine CL and the role of prostaglandin E2 (PGE2) in regulation of its function: An in vivo approach

“…Thus, formation of the canine CL is associated with increased cyclooxygenase 2 (COX2, PTGS2) and PGE2 synthase (PGES, PTGES) expression [10][11][12], accompanying progressively increasing expression levels of the steroidogenic acute regulatory protein (STAR) and 3b-hydroxysteroid dehydrogenase (3bHSD, HSD3B2) and dynamically rising circulating P4 levels. In line with these findings, we were able to show that the PTGES-derived PGE2 significantly upregulates P4 synthesis in canine luteal cells isolated from the early CL [13]. This effect seems to be mediated at the level of STAR-dependent steroid substrate provision, rather than at the level of enzymatic activity of 3bHSD and P450 side-chain cleavage enzyme (P450scc, CYP11A1), as concluded from their unaltered expression in response to treatment with PGE2.…”

“…The previously postulated [10,11,13] causality between the COX2 and the PGES-dependent synthesis of PGE2 regulating STAR protein expression and function has now been clearly shown. Thereby, the direct role of PGE2 in regulating early canine CL function, as characterized by decreased sensitivity toward gonadotropic stimuli, has been further substantiated.…”

“…The mRNA obtained from a previous study [13] was used in the present experiments to gain additional information on PRLR mRNA expression in canine lutein cells in response to PGE2 treatment. In that study, canine primary lutein cells were isolated from 15 healthy bitches submitted for routine ovariohysterectomies, which were performed during the early luteal phase, 7 to 14 days after the clinical signs of heat had ceased.…”

“…Additionally, taking into account the role of PRL as the main luteotrophic factor during the second half of canine diestrus, and the recently presented evidence showing increasing expression of its receptor during the early luteal phase [18], the expression of PRLR was investigated by assessing messenger RNA (mRNA) obtained from primary luteal cells isolated during the early luteal phase, which had been treated with PGE2 in previous experiments [13].…”

The Dog: Nonconformist, Not Only in Maternal Recognition Signaling

“…The endocrine and molecular mechanisms regulating luteal function in the dog have been extensively discussed recently (Hoffmann et al 2004b ;Concannon 2011Concannon , 2012Papa and Hoffmann 2011 ;Kowalewski 2012Kowalewski , 2014Kowalewski et al 2013 ).…”