Brain‐derived neurotrophic factor improves proliferation of endometrial epithelial cells by inhibition of endoplasmic reticulum stress during early pregnancy

Abstract

Brain-derived neurotrophic factor (BDNF) is a member of the neurotrophin family binds to two transmembrane receptors; neurotrophic receptor tyrosine kinase 2 (NTRK2) with high affinity and p75 with low affinity. Although BDNF-NTRK2 signaling in the central nervous system is known, signaling in the female reproductive system is unknown. Therefore, we determined effects of BDNF on porcine endometrial luminal epithelial (pLE) cells isolated from Day 12 of pregnancy, as well as expression of BDNF and NTRK2 in endometria of cyclic and pregnant pigs. BDNF-NTRK2 genes were expressed in uterine glandular (GE) and luminal (LE) epithelia during early pregnancy. In addition, their expression in uterine GE and LE decreased with increasing parity of sows. Recombinant BDNF increased proliferation in pLE cells in a dose-dependent, as well as expression of PCNA and Cyclin D1 in nuclei of pLE cells. BDNF also activated phosphorylation of AKT, P70S6K, S6, ERK1/2, JNK, P38 proteins in pLE cells. In addition, cell death resulting from tunicamycin-induced ER stress was prevented when pLE cells were treated with the combination of tunicamycin and BDNF which also decreased cells in the Sub-G phase of the cell cycle. Furthermore, tunicamycin-induced unfolded protein response genes were mostly down-regulated to the basal levels as compared to non-treated pLE cells. Our finding suggests that BDNF acts via NTRK2 to induce development of pLE cells for maintenance of implantation and pregnancy by activating cell signaling via the PI3K and MAPK pathways and by inhibiting ER stress.

Fibroblast growth factor 2 induces proliferation and distribution of G2/M phase of bovine endometrial cells involving activation of PI3K/AKT and MAPK cell signaling and prevention of effects of ER stress

“…And, ER stress disrupts placentation and increases intrauterine growth restriction through regulating post‐translational processing of proteins (Yung et al, ). Furthermore, ER stress reduces proliferation of porcine endometrial cells through activation of UPR factors (Lim, Bae, Bazer, & Song, ). In accordance with previous reports, results of present study indicated that ER stress induced by tunicamycin, reduced proliferation of BEND cells which was reversed by FGF2.…”

Impact of negative energy balance on transcriptomic profiles of three endometrial cell types isolated by laser capture microdissection in postpartum dairy cows

“…Contrary to the porcine endometrium where its expression was located in epithelial cells, NTRK2 was mainly expressed here in stromal cells [57]. The expression of the NTRK2 gene, which encodes the receptor of brain derived neurotrophic factor, is conserved in mammalian uterus but its signalling function is not yet understood in the female reproductive system [58].…”

miR‐182 selectively targets HOXA10 in goat endometrial epithelium cells in vitro

“…What's more, HOXA10 was regulated by many factors in EECs, including sex hormones (Taylor, Arici, Olive, & Igarashi, ; Wu et al., ; Zhong, Wang, & Liu, ), conceptus secretions (Blitek, Morawska, Kiewisz, & Ziecik, ) under normal physiological conditions. More importantly, variety of factors participated in the regulation of EECs under normal physiological conditions, including E2 (Shan, Li, Yang, & Li, ), P4 (Kyo et al., ), integrins (Park et al., ), periostin (Zheng et al., ), non‐esterified fatty acids (Chankeaw et al., ), growth factor (Islam, Yamagami, Yoshii, & Yamauchi, ), brain‐derived neurotrophic factor (Lim, Bae, Bazer, & Song, ). Moreover, HOXA10 was regulated by multiple miRNAs, such as miR‐135 in endometriosis (Petracco et al., ), miR‐494 in oral cancer (Libóriokimura, Jung, & Chan, ), miR‐218 in hepatocellular carcinoma cell (Zhong‐Di Xiao et al., ).…”