PT  - JOURNAL ARTICLE
AU  - Deborah P. Fischer
AU  - Anna L. Griffiths
AU  - Sylvia Lui
AU  - Uzmah J. Sabar
AU  - Diane Farrar
AU  - Peter J. O’Donovan
AU  - David F. Woodward
AU  - Kay M. Marshall
TI  - Distribution and Function of Prostaglandin E<sub>2</sub> Receptors in Mouse Uterus: Translational Value for Human Reproduction
AID  - 10.1124/jpet.119.263509
DP  - 2020 Jun 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 381--390
VI  - 373
IP  - 3
4099  - http://jpet.aspetjournals.org/content/373/3/381.short
4100  - http://jpet.aspetjournals.org/content/373/3/381.full
SO  - J Pharmacol Exp Ther2020 Jun 01; 373
AB  - 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.SIGNIFICANCE STATEMENT This research validates the use of nonpregnant mice for preclinical drug discovery of uterine EP receptor targets. To determine the utility of novel drugs and delivery systems at term pregnancy and labor, pharmacological agents interacting with EP3 receptors have clear translational value.