Urocortins exhibit differential effects on PGE2 and PGF2α output via CRHR2 in human myometrium

Abstract

Urocortins (UCNs), belonging to corticotropin-releasing hormone (CRH) family, exert their function via CRH receptor type 1 (CRHR1) and 2 (CRHR2). Our previous studies have demonstrated that CRH acts on CRHR1 to potentiate prostaglandins (PGs) output induced by inflammatory stimuli in myometrial cells. In the present study, we sought to investigate the effects of UCNs on prostaglandin (PG) output via CRHR2 in cultured human uterine smooth muscle cells (HUSMCs) from pregnant women at term. We found that UCN and UCN 3 treatment promoted PGE2 and PGF2α secretion in a dose-dependent manner. In contrast, UCN2 dose-dependently inhibited PGE2 and PGF2α secretion. Their effects were reversed by CRHR2 antagonist and CRHR2 siRNA. Mechanically, we showed that UCN and UCN3 suppressed cAMP production and led to Gi activation while UCN2 stimulated cAMP production and activated Gs signaling. Further, UCN and UCN3 but not UCN2 activated NF-κB and MAPK signaling pathways through Gi signaling. UCN and UCN3 stimulation of PGs secretion were dependent on Gi/adenylyl cyclase (AC)/cAMP, NF-κB and MAPK signaling pathways. UCN2 suppression of PGs output was through Gs/AC/cAMP signaling pathways. Our data suggest that UCN, UCN2 and UCN3 can finely regulate PGs secretion via CRHR2, which facilitates the functional status of the uterus during pregnancy.

Linking stress with urocortin in rats

“…Increased Urocortin"s after chronic variable stress is in accordance with the findings of [ 26 , 27 ] where stress induces neurodegenerative process with in the limbic system and hippocampus which causes more detrimental effects by high production of glucocorticoids which leads to the production of free radicals in the neurons because of oxidative stress [ 26 , 27 ]. It has been postulated that glucocorticoids regulate CRF transcription via a cAMP-responsive element (CRE) present in the promoter of the CRF-gene [ 28 ] Since CRE is also present in the promoter of the mouse UCN1 gene it might be a target for glucocorticoids to regulate UCN1-gene expression [ 29 ]. On the other hand, the expression of UCN2 in the mouse hypothalamus and brainstem appears to be controlled by glucocorticoids via a glucocorticoid-responsive element (GRE) in the Ucn2-gene promoter were reported [ 30 , 31 ].…”

Integrated Serum Pharmacochemistry, Metabolomics, and Network Pharmacology to Reveal the Material Basis and Mechanism of Danggui Shaoyao San in the Treatment of Primary Dysmenorrhea

“…It was mainly due to the decrease of progesterone secretion and the release of arachidonic acid before menstruation in patients with dysmenorrhea, which was oxidized to PGs under the action of cyclooxygenase. When prostaglandin secretion is excessive, it will induce the contraction of blood vessels and myometrium, resulting in ischemia and pain ( You et al, 2021 ). In addition, increasing prostaglandin levels may also improve the perception of peripheral neuralgia ( Cruz et al, 2012 ).…”