Erythropoietin-producing hepatocellular receptor A7 restrains estrogen negative feedback of luteinizing hormone via ephrin A5 in the hypothalamus of female rats

Abstract

We have previously shown that systemic injection of erythropoietin-producing hepatocellular receptor A7 (EPHA7)-Fc raises serum luteinizing hormone (LH) levels before ovulation in female rats, indicating the induction of EPHA7 in ovulation. In this study, we aimed to identify the mechanism and hypothalamus-pituitary-ovary (HPO) axis level underlying the promotion of LH secretion by EPHA7. Using an ovariectomized (OVX) rat model, in conjunction with low-dose 17β-estradiol (E2) treatment, we investigated the association between EPHA7-ephrin (EFN)A5 signaling and E2 negative feedback. Various rat models (OVX, E2-treated OVX, and abarelix treated) were injected with the recombinant EPHA7-Fc protein through the caudal vein to investigate the molecular mechanism underlying the promotion of LH secretion by EPHA7. Efna5 was observed strongly expressed in the arcuate nucleus of the female rat by using RNAscope in situ hybridization. Our results indicated that E2, combined with estrogen receptor (ER)α, but not ERβ, inhibited Efna5 and gonadotropin-releasing hormone 1 ( Gnrh1) expressions in the hypothalamus. In addition, the systemic administration of EPHA7-Fc restrained the inhibition of Efna5 and Gnrh1 by E2, resulting in increased Efna5 and Gnrh1 expressions in the hypothalamus as well as increased serum LH levels. Collectively, our findings demonstrated the involvement of EPHA7-EFNA5 signaling in the regulation of LH and the E2 negative feedback pathway in the hypothalamus, highlighting the functional role of EPHA7 in female reproduction.

Comparative Transcriptomic Analysis of Hu Sheep Pituitary Gland Prolificacy at the Follicular and Luteal Phases

“…In our study, XR_001042176.3 can cis-regulate EPHA7 , which was upregulated at luteal phase. Previous research demonstrated the involvement of EPHA7-EFNA5 signaling in the regulation of the LH and E2 negative-feedback pathways in the hypothalamus [ 41 ], highlighting the functional role of EPHA7 in female reproduction [ 42 ]. We also found that lncRNA MSTRG.8143.5, which was upregulated at the follicular phase, simultaneously targeted DLL1 , EGR1 , GH1 , DUSP1 and NTRK2 in the sheep pituitary gland.…”

Effects of Decamethylcyclopentasiloxane on Reproductive Systems in Female Rats

“…GTH acts on the ovary to increase the secretion of steroid hormones, including estradiol (E2) and progesterone (P4) [3]. Enhanced steroid hormones inhibit the activity of the hypothalamus and pituitary gland [4].…”