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Oxytocin Receptor Development in Ovine Uterus and Cervix Throughout Pregnancy and at Parturition As Determined by in Situ Hybridization Analysis D

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Oxytocin Receptor Development in Ovine Uterus and Cervix Throughout Pregnancy and at Parturition As Determined by in Situ Hybridization Analysis D Oxytocin receptor development in ovine uterus and cervix throughout pregnancy and at parturition as determined by in situ hybridization analysis D. C. Wathes, H. Flick Smith, S. T. Leung,, K. R. Stevenson, S. Meier and G. Jenkin Babraham Institute, Babraham, Cambridge CB2 4AT, UK; ^Department of Farm Animal and Equine Medicine and Surgery, Royal Veterinary College, Hawkshead Road, Potters Bar, Herts EN6 1NB, UK; and Department of Physiology, Monash University, Clayton, Victoria 3168, Australia The development of uterine oxytocin receptors is an important regulatory step in the initiation of labour. Paracrine production of oxytocin by uterine and placental tissues may also be involved in some species. Placentome, intercotyledonary endometrium, myometrium and fetal membranes were collected from 3\p=n-\5ewes each, at regular intervals throughout pregnancy and from eight ewes during labour. Localization of mRNA encoding oxytocin and its receptor was by in situ hybridization; oxytocin peptide concentrations were measured by radioimmunoassay and oxytocin receptor concentrations were measured by autoradiography and radioreceptor assay. In the intercotyledonary endometrium, mRNA encoding the oxytocin receptor was located in the luminal epithelium only. Both the epithelial and myometrial receptors were detected at low concentrations from the fourth week of gestation onwards, with a major increase associated with the onset of labour. In the placentomes, oxytocin receptors were localized to a stromal capsule surrounding the placental villi. Expression in this region was maximal in mid-gestation, declining in the second half of pregnancy and remaining low during labour. Cervical oxytocin receptors were detected at low concentrations in the epithelium and the muscular/connective tissue layers from day 22 of pregnancy onwards. There was no evidence for the local uterine production of oxytocin in the ewe; mRNA encoding oxytocin was undetectable and oxytocin concentrations were always < 23 pg g \m=-\1wet mass of tissue. These results suggest that regulation of the timing of oxytocin receptor development varies between the different tissue types, despite a similar steroidal background. The receptors in the luminal epithelium are probably associated with the ability of exogenous oxytocin to induce the release of PGF2\g=a\throughout most of pregnancy. The increase in receptors in both the intercotyledonary endometrium and myometrium at term suggest an involvement in labour, whereas their role in caruncular stroma in mid-pregnancy is unknown. Introduction whereas vaginocervical stimulation caused by passage of the lamb at birth leads to a more pronounced rise (Mitchell el al, an role Oxytocin plays important in parturition, acting as a 1982; Kendrick et al, 1991). It is, however, uncertain whether potent myometrial stimulant at picomolar concentrations increased oxytocin release from the neurohypophysis triggers (Fuchs, 1985). In addition, there is evidence from a variety of the onset of labour. In this respect, the marked increase in the species, including humans (Fuchs et al, 1982) and sheep concentration of oxytocin receptors in both endometrium and et that it can increase the and (Mitchell al, 1975), synthesis myometrium at this time may be more important (Fuchs, 1985). release of via an action on in the prostaglandin F2a receptors The first evidence for an extra-hypothalamic source of endometrium. and immunoreactiv¬ Oxytocin gene expression oxytocin synthesis came from studies on the ovine corpus ity in the paraventricular and supraoptic nuclei of the ewe rise luteum (Ott and Scott, 1910; Wathes and Swann, 1982). In late with further in gestation a increase at term (Broad et al, ruminants, luteal oxytocin synthesis is initiated at the time of 1993). There is a modest increase in the plasma concentration ovulation, and concentrations of mRNA and peptide peak in of associated with the onset of uterine oxytocin contractions, the early and mid-luteal phases, respectively (for review, see *Address for correspondence. Wathes and Denning-Kendall, 1992), but decline and remain Received 5 July 1995. low during gestation (Sheldrick and Flint, 1983). More recent Downloaded from Bioscientifica.com at 09/23/2021 08:38:09PM via free access 24 ti — —H·—'-~"-.imi .-*.»m" * ii n »in - 12h 1-i»i| ». m-1-ny| fm-—*- Hq'»W|-^-*- · ' ' 3h «!-L— H""·'" *»" j|,»»t<'» »f» »-1 p»»-{-#--' M »—" I» Labour M fr<·' m *»·***» fr > t ufi »4»" 10 min Fig. 1. Representative trace of uterine electromyographic activity recorded from a ewe on day 148—149 of gestation before and during the onset of labour. Tissue was collected after the development of high frequency, high amplitude contractions. studies in other species have shown that oxytocin can also be oestrus (day 0). The reproductive tracts were removed after synthesized by both the endometrium and placenta of rats and administration of an overdose of pentobarbitone sodium humans, with concentrations increasing at term (Lefebvre et al, (Lethobarb: Duphar Veterinary Ltd, Southampton) at the fol¬ 1992; Chibbar et al, 1993). This suggests that there is a lowing time points during pregnancy: days 13—14 (n = 6), day paracrine loop between peptide and receptor within the par¬ 22 (»1 = 5), days 30-35 (rt = 4), days 45-55 (n = 4), day 70 turient uterus and may obviate the need for oxytocin of (n = 3), day 105 (n = 3), days 138-140 (n = 4), during labour on neurohypophyseal origin to act as an initiating stimulus for day 148.8 ± 0.5 (n = 8), 1-2 h post partum (n = 4) and day 2 parturition. post partum (n = 1). In the uteri and oviducts of nonpregnant ewes, oxytocin receptor concentrations increase at luteolysis to reach peak concentrations at oestrus, before declining again in the early Electromyographic recordings luteal (Roberts et al, 1976; Sheldrick and Flint, 1985; phase The time of the onset of labour was established by fitting el al, At oestrus, are in Ayad 1990). oxytocin receptors present ewes with uterine EMG electrodes between the luminal caruncular eight recording epithelium, glands, stroma and day 117 and day 121 of gestation. Electrodes made of myometrium (Ayad et al, 1991; Wathes and Hamon, 1993; multistranded stainless steel Teflon-coated wire (1.2 m long; Stevenson et al, 1994). Administration of exogenous oxytocin Cooner Wire Co., Chatsworth, CA), covered with a vinyl can stimulate release of the metabolite PGF2ct 13,14,dihydro- catheter (Durai Plastics and Engineering, Durai, NSW) were 15-keto (PGFM) from the endometrium into prostaglandin F2a sutured to the body of the uterus in a triangular pattern 5 mm the circulation of ewes at luteolysis and peripheral nonpregnant apart. Signals derived from these electrodes were amplified on from about 17 of onwards (Meier et al, 1995). day gestation a Grass 7P3 amplifier (Grass Instruments, Quincey, MA) with Oxytocin has also been in the control of myometrial implicated high pass filtering at 0.3 Hz. These signals were recorded on a contractions at oestrus (Gilbert et al, 1992) and during preg¬ two or four channel Grass Polygraph (Model 7D). Electromyo¬ (Nathanielsz, 1973; et al, 1984). for nancy Lye Receptors graphic activity was monitored throughout the later stages of are also in the cervix of ewes oxytocin present nonpregnant and the animals were characterized as in and and pregnancy being (Matthews Ayad, 1994), changes in the electromyo¬ labour when the contractile activity recorded showed continu¬ (EMG) of the cervix have been recorded at graphic activity ous contractions with a low of It high frequency, high amplitude different stages gestation (Garcia-Villar et al, 1984). is duration (Harding et al, 1982; Jenkin and Nathanielsz, 1994). therefore that oxytocin could modulate the of possible activity Tissue collection was performed when this type of EMG the tract reproductive during pregnancy. activity was observed with visual observations of The the together purpose of present study was to determine the cervical opening (Fig. 1). localization and concentration of oxytocin receptors in the ovine uterus, placenta and cervix throughout gestation, and to investigate whether the uterus or placenta are sources of local Tissue collection oxytocin synthesis in this species. The reproductive tract was removed immediately after slaughter. In early pregnancy (days 13-30), whole transverse Materials and Methods sections of uterine horn and cervix approximately 1.5 cm long were cut, wrapped in aluminium foil, frozen in isopentane cooled in liquid N2 and stored at 80°C. At later stages, Animals - whole placentomes, half placentomes, sections of uterine wall Ewes of various breeds with an average duration of ges¬ (comprising both intercotyledonary endometrium and myo¬ tation of 147 ± 2.5 days (mean ± sd) were mated at natural metrium) and cervix were frozen separately. Additional pieces Downloaded from Bioscientifica.com at 09/23/2021 08:38:09PM via free access of placentome, intercotyledonary endometrium, myometrium Membranes (50 pg protein per tube) were incubated with and allantochorion were also collected for determination of [3,5-3H-Tyr]oxytocin (5 nmol I"1, 1224 GBq mmol; NEN oxytocin binding capacity and peptide extraction. Research Products) in 0.1ml Tris-HCl buffer (25 mmol 1_1 pH 7.6, containing 0.1% (w/v) BSA). Nonspecific binding was determined in the of 10 1 . presence pmol oxytocin ~ Initial Reagents experiments were performed to determine the optimum incu¬ bation time and cation concentration. All data here Chemicals were purchased from Chemical Co. (Poole,
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