Changing prostaglandin E2 (PGE₂) signaling during lesional progression and exacerbation of endometriosis by inhibition of PGE₂ receptor EP2 and EP4.

ABSTRACT:

Purpose

We investigated the change, if any, in prostaglandin E2 (PGE₂) signaling in endometriotic lesions of different developmental stages in mouse. In addition, we evaluated the effect of treatment of mice with induced deep endometriosis (DE) with inhibitors of PGE₂ receptor subtypes EP2 and EP4 and metformin.

Methods

Three mouse experimentations were conducted. In Experiment 1, female Balb/C mice were induced with endometriosis or DE and were serially sacrificed after induction. Experiments 2 and 3 evaluated the effect of treatment with EP2 and EP4 inhibitors and metformin, respectively, in mice with induced DE. Immunohistochemistry analysis of COX-2, EP2, and EP4, along with the extent of lesional fibrosis, was evaluated.

Results

The immunostaining of COX-2, EP2, and EP4 turned from activation to a stall as lesions progressed. Treatment with EP2/EP4 inhibitors in DE mice exacerbated endometriosis-associated hyperalgesia and promoted fibrogenesis in lesions even though it suppressed the PGE₂ signaling dose-dependently. In contrast, treatment with metformin resulted in increased PGE₂ signaling, concomitant with improved hyperalgesia, and retarded lesional fibrogenesis.

Conclusions

The PGE₂ signaling diminishes as endometriotic lesions progress. Treatment with EP2/EP4 inhibitors in DE mice exacerbates endometriosis, but metformin appears to be promising seemingly through the induction of the PGE₂ signaling.

SUBMITTER: Huang Q 

PROVIDER: S-EPMC8660993 | biostudies-literature |

REPOSITORIES: biostudies-literature