Fischer, Deborah P;
Griffiths, Anna L;
Lui, Sylvia;
Sabar, Uzmah J;
Farrar, Diane;
O’Donovan, Peter J;
Woodward, David F;
(2020)
Distribution and Function of Prostaglandin E2 Receptors in Mouse Uterus: Translational Value for Human Reproduction.
The Journal of Pharmacology and Experimental Therapeutics
, 373
(3)
pp. 381-390.
10.1124/jpet.119.263509.
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Abstract
Prostaglandin (PG) E analogs are used clinically to ripen the cervix and induce labor. However, selective receptor agonists may have potential to improve induction response rates or manage unwanted uterine hypercontractility in conditions such as dysmenorrhea and preterm labor. To characterize their therapeutic value, PGE2 analogs were used to investigate the functional E‐type prostanoid (EP) receptor population in isolated human uterus. Responsiveness in mouse tissues was also examined to validate its use as a preclinical model. Uterine samples were obtained from mice at dioestrus (n = 12), term gestation (n = 14), and labor (n = 12) and from the lower uterus of women undergoing hysterectomy (n = 12) or Caesarean section (n = 18). Vehicle and agonist effects were assessed using superfusion and immersion techniques. PGE2 evoked predominant excitatory responses in mouse and relaxation in human tissues. Selective EP4 agonists inhibited tissue activity in both nonpregnant species, while the EP2 mimetic CP533536 also attenuated uterine contractions throughout gestation. The uterotonic effects of the EP3/1 agonist sulprostone were more pronounced than the EP1 agonist ONO-D1-004, corresponding to abundant EP3 receptor expression in all samples. The contractile phenotype in mouse compared with human uteri may relate to regional differences as well as high expression of EP3 receptor transcripts. Similarities in nonpregnant and gestational tissues across species suggest that EP3 may represent a valuable translational drug target for preventing uterine hypercontractility by employing a selective antagonist.
| Type: | Article |
|---|---|
| Title: | Distribution and Function of Prostaglandin E2 Receptors in Mouse Uterus: Translational Value for Human Reproduction |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1124/jpet.119.263509 |
| Publisher version: | https://doi.org/10.1124/jpet.119.263509 |
| Language: | English |
| Additional information: | Copyright © 2020 by The Author(s). This is an open access article distributed under the CC BY-NC Attribution 4.0 International license, https://creativecommons.org/licenses/by/4.0/. |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > Inst of Clinical Trials and Methodology UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > Inst of Clinical Trials and Methodology > MRC Clinical Trials Unit at UCL |
| URI: | https://discovery-pp.ucl.ac.uk/id/eprint/10178249 |
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