Investigation of the Role of Pituitary Adenylate Cyclase-Activating Peptide (PACAP) and Its Type 1 (PAC1) Receptor in Uterine Contractility during Endometritis in Pigs

Abstract

Uterine inflammation is a common pathology in animals, leading to disturbances in reproductive processes and reduced production profitability. Pituitary adenylate cyclase-activating peptide (PACAP) effects at the uterine level during inflammation are not known. In the current study, we analyzed the relative PACAP type 1 receptor (PAC1R) mRNA transcript and protein abundances in the myometrium (MYO), as well s PACAP and PAC1R involvement in the contractile function of inflamed pig uterus. To that end, E. coli suspension (E. coli group) or saline (SAL group) was injected into the uterine horns or laparotomy was performed (CON group). Eight days after the bacteria injections, severe acute endometritis and a reduced relative abundance of PAC1R protein in the MYO were observed. Compared to the period before PACAP in vitro administration, PACAP (10−7 M) in the CON and SAL groups decreased in amplitude in the MYO and endometrium (ENDO)/MYO, whereas in the E. coli group, increased amplitude in the MYO and reduced amplitude in the ENDO/MYO were observed. In the E. coli group, PACAP enhanced the amplitude in the MYO (10−7 M) and decreased the amplitude in the ENDO/MYO (10−8 M) compared with other groups. PACAP (10−7 M) increased the frequency of both kinds of strips in the CON and SAL groups compared with the pretreatment period. PACAP (both doses) did not significantly change the frequency in the E. coli group, whereas in response to PACAP (10−7 M), the frequency was reduced compared to other groups. In the MYO, PAC1R antagonist decreased the amplitude reduction (CON and SAL groups) and reversed a rise in PACAP (10−7 M)-evoked amplitude (E. coli group). PAC1R blocking reversed (MYO) and abolished (ENDO/MYO) the stimulatory effect of PACAP (10−7 M) on the frequency (CON and SAL groups). PAC1R antagonist and PACAP (10−7 M) evoked the appearance of frequency depression in both kinds of strips (E. coli group). In summary, in pigs, severe acute endometritis reduces the relative abundance of PAC1R protein in the MYO, and PAC1R mediates the influence of PACAP on inflamed uterus contractility.

Female reproductive functions of the neuropeptide PACAP

“…PAC1 receptor mRNA has been recently demonstrated in the uterus of healthy pigs, and the abundance of PAC1 receptor protein was reduced in inflammatory conditions ( 103 ). Endometrial inflammation also leads to changes in PACAP expression of the dorsal root ganglia supplying the porcine uterus ( 104 ).…”

“…There are only a few studies dealing with the actions of PACAP in the uterus and placenta. According to a recent study, PACAP treatment leads to decrease of amplitude and an increase in frequency of myometrium contraction in pigs ( 103 ). Effects of PACAP on blood vessels and smooth muscle contractility in the uteroplacental unit was also thoroughly investigated.…”

Molecular Links between Sensory Nerves, Inflammation, and Pain 2.0

“…Several PACAPinduced intracellular pathways and signaling mechanisms were identified in cultured rat trigeminal ganglia primary sensory neurons related to cytokines, oxidative stress, and mitochondrial dysfunction, which are independent of the known and cloned PAC1 receptors [12]. Jana and co-workers described the role of PACAP in the inflamed pig uterus and showed that severe acute endometritis decreased PAC1 receptor expression in the myometrium, leading to decreased contractility [13].…”