Molecular Mechanism of Equine Endometrosis: The NF-κB-Dependent Pathway Underlies the Ovarian Steroid Receptors’ Dysfunction

Abstract

Endometrosis is a frequently occurring disease decreasing mares’ fertility. Thus, it is an important disease of the endometrium associated with epithelial and stromal cell alterations, endometrium gland degeneration and periglandular fibrosis. Multiple degenerative changes are found in uterine mucosa, the endometrium. However, their pathogenesis is not well known. It is thought that nuclear factor-κB (NF-κB), a cell metabolism regulator, and its activation pathways take part in it. The transcription of the profibrotic pathway genes of the NF-κB in fibrotic endometria differed between the follicular (FLP) and mid-luteal (MLP) phases of the estrous cycle, as well as with fibrosis progression. This study aimed to investigate the transcription of genes of estrogen (ESR1, ESR2) and progesterone receptors (PGR) in equine endometria to find relationships between the endocrine environment, NF-κB-pathway, and fibrosis. Endometrial samples (n = 100), collected in FLP or MLP, were classified histologically, and examined using quantitative PCR. The phase of the cycle was determined through the evaluation of ovarian structures and hormone levels (estradiol, progesterone) in serum. The transcription of ESR1, ESR2, and PGR decreased with the severity of endometrial fibrosis and degeneration of the endometrium. Moreover, differences in the transcription of ESR1, ESR2, and PGR were noted between FLP and MLP in the specific categories and histopathological type of equine endometrosis. In FLP and MLP, specific moderate and strong correlations between ESR1, ESR2, PGR and genes of the NF-κB pathway were evidenced. The transcription of endometrial steroid receptors can be subjected to dysregulation with the degree of equine endometrosis, especially in both destructive types of endometrosis, and mediated by the canonical NF-κB pathway depending on the estrous cycle phase.

17β‐Estradiol mediates TGFBR3/Smad2/3 signaling to attenuate the fibrosis of TGF‐β1‐induced bovine endometrial epithelial cells via GPER

“…It has been demonstrated that estrogens exert their actions by binding to the estrogen receptor. Except the classic nuclear receptors ERα and ERβ, which have been detected in uteri and the expression of ERα and ERβ in the endometrium is changed in relation to the phase of the ovarian cycle and endometrial disease (Jasiński et al, 2022; Schams & Berisha, 2002), the estrogen membrane receptor GPER was also detected in the uteri (Kolkova et al, 2010). Our results showed that GPER was expressed in the bovine endometrium, and its expression level was significantly higher in the healthy endometria than that in the endometria with endometritis.…”

Genomic screening of allelic and genotypic transmission ratio distortion in horse

“…Indeed, a study provided evidence that thyroid hormones dysregulation alters NOSs profiles, which suggested that NOSs/NO is possibly involved in the regulation of female reproduction [71]. Recent studies have reported the relation of nuclear factor kappaB (NF-κB) with endometrosis, a serious problem that mainly affects the fertility of older mares [72][73][74]. And one of the genes associated with a region with TRD is the RELA gene that belongs to the subunits NF-κB.…”