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  • Although it is well established that estrogen and ESR

    2019-08-12

    Although it is well established that estrogen and ESR1 mediate numerous reproductive processes, increasing evidence suggests that ESR2 also lays an integral role in reproduction. ESR2 is a mediator in folliculogenesis and may also act by stimulating ovulation and regulating luteinization (Su et al., 2012). A paper by Su et al., showed an increased expression of ESR2 compared to ESR1 in human myometrium and cervix during pregnancy (Su et al., 2012); however, our results showed a similar expression of ESR2 during estrus and late pregnancy, including a similar receptor protein localization for all reproductive stages evaluated. Again, estrogens are greatly increased during late pregnancy in the mare (Conley, 2016), potentially over-riding the need for an increased receptor concentration. In addition to estrogen-induced collagenase expression, PGE2 also affects cervical relaxation through effects on cervical collagen and smooth muscle (Ji et al., 2008). Collagen dispersion is initiated by PGE2, allowing the cervical canal to dilate in cattle (Mizrachi and Shemesh, 1999) and in sheep (Leethongdee et al., 2010). Our results showed a higher expression of PTGER2 in the cervical stroma of late pregnant mares, compared to estrus and diestrus, suggesting that the cervix is readying itself for parturition and the associated increase in prostaglandins. Using immunohistochemistry, we found that EP2 and EP4 receptors themselves were localized in the nuclei and cytoplasm of endocervical epithelium, as well as in the cytoplasm of smooth muscle. This is consistent with the finding that PGE2 is produced and secreted by vascular endothelium, squamous and glandular epithelium, serosa, mesenchymal cells, as well as circular and longitudinal smooth muscle (Gu et al., 2012) in the cervix. These observations were confirmed by Hinton et al. in rats (Hinton et al., 2010) and Schmitz et al. in sheep (Schmitz et al., 2006). Fortier et al. first hypothesized that the epithelial already were the principal source of PGE2 (Fortier et al., 1988). Later, Silva et al. localized PTGER2 and PTGER4 receptors in the cytoplasm of luminal and glandular epithelium within endometrium and cytoplasm of myometrial smooth muscle in mares (Silva et al., 2014). Both PTGER2 and PTGER4 are classified as relaxant receptors which are G protein-coupled receptors which act to stimulate adenylate cyclase and induce already smooth muscle relaxation by elevating cyclic adenosine monophosphate production (Sugimoto and Narumiya, 2007). Moreover, PTGER4 is known to regulate matrix metalloproteinase secretion and expression, thereby aiding in the process of cervical ripening (Chien and MacGregor, 2003). Thus, the presence of the relaxant receptors in the epithelial tissue and smooth muscle infers that, in the horse, prostaglandins are intimately involved in the ripening of the cervix, also confirmed by (Volkmann et al., 1995). In the current study, expression of PTGER4 was not different between late pregnancy and cyclic mares, despite the increase in PTGER2 seen during this time. The lack of change in PTGER4 was likely due to these samples being taken prior to 10 months of gestation, well before the anticipated onset of prepartum changes in the mare. In goats, PCR quantitation of PTGER2 and PTGER4 indicates that the levels of the mRNAs are significantly higher in intrapartum than in nonpregnant and midpregnant cervices (Gu et al., 2012). Prostaglandins are local mediators synthesized in a multi-step pathway from arachidonic acid, a pathway which includes cyclooxygenases. PGE2 plays a central role in parturition, contributing to uterine contractility, membrane rupture, and cervical ripening (Olson, 2003). Prepartum changes in the cervix during late gestation appears to be a gradual process that precedes the uterine contractions by several weeks (Word et al., 2007). Cervical ripening has been related to inflammatory changes that are described as the final pathway to parturition (House et al., 2009). In this experiment, mares between 286 to 298days of gestation showed an upregulation of PTGS1 in mucosa and PTGS2 in cervical stroma compared to estrous mares. This suggests a possible activation of the arachidonic acid pathway, with formation of precursors which will help initiate the onset of parturition.