Emerging roles of APLN and APELA in the physiology and pathology of the female reproductive system

Abstract

APLN, APELA and their common receptor APLNR (composing the apelinergic axis) have been described in various species with extensive body distribution and multiple physiological functions. Recent studies have witnessed emerging intracellular cascades triggered by APLN and APELA which play crucial roles in female reproductive organs, including hypothalamus-pituitary-gonadal axis, ovary, oviduct, uterus and placenta. However, a comprehensive summary of APLN and APELA roles in physiology and pathology of female reproductive system has not been reported to date. In this review, we aim to concentrate on the general characteristics of APLN and APELA, as well as their specific physiological roles in female reproductive system. Meanwhile, the pathological contexts of apelinergic axis dysregulation in the obstetrics and gynecology are also summarized here, suggesting its potential prospect as a diagnostic biomarker and/or therapeutic intervention in the polycystic ovary syndrome, ovarian cancer, preeclampsia and gestational diabetes mellitus.

Keywords: APELA; APLN; APLNR; Female; Function.

Figure 1. Expression and function of APLN and APELA in reproduction system.

(A) In physiological conditions, APLN (in blue textbox) and APELA (in green textbox) play diverse roles at the different parts of the ovary, uterus and placenta. (B) In pathological conditions, aberrant expression of APLN (in orange textbox) and APELA (in purple textbox) lead to female reproductive disorders such as polycystic ovary syndrome (PCOS), ovarian cancer, preeclampsia (PE), gestational diabetes mellitus (GDM) and endometriosis. * indicating potential apelinergic stimulating factors. ? indicating still unclear or controversy about the functions or contributions of apelinergic molecules in these diseases. ↑ and ↓ in the textbox means increase and decrease respectively, both indicate statistically significant changes. → means resulting.

Figure 2. Intracellular signaling pathways and physiological functions of APLN and APELA.

(A) Both APLN (in blue) and APELA (in orange) can classically activate Gαi/o and Gαq/11 mediated intracellular transduction via binding to their common receptor APLNR. (B) Non-coding APELA binds to hnRNPL and promotes p53-mediated cell apoptosis. (C) APELA also stimulates PI3K-independent NODAL/TGFβ signal through alternative receptors in hESCs. AC, adenylate cyclase; eNOS, endothelial nitric oxide synthase; IncRNA, long non-coding RNA; hnRNPL, heterogeneous nuclear ribonucleoprotein L.