Apelin, APJ, and ELABELA: Role in Placental Function, Pregnancy, and Foetal Development-An Overview

Abstract

The apelinergic system, which includes the apelin receptor (APJ) as well as its two specific ligands, namely apelin and ELABELA (ELA/APELA/Toddler), have been the subject of many recent studies due to their pleiotropic effects in humans and other animals. Expression of these factors has been investigated in numerous tissues and organs-for example, the lungs, heart, uterus, and ovary. Moreover, a number of studies have been devoted to understanding the role of apelin and the entire apelinergic system in the most important processes in the body, starting from early stages of human life with regulation of placental function and the proper course of pregnancy. Disturbances in the balance of placental processes such as proliferation, apoptosis, angiogenesis, or hormone secretion may lead to specific pregnancy pathologies; therefore, there is a great need to search for substances that would help in their early diagnosis or treatment. A number of studies have indicated that compounds of the apelinergic system could serve this purpose. Hence, in this review, we summarized the most important reports about the role of apelin and the entire apelinergic system in the regulation of placental physiology and pregnancy.

Keywords: adipokines; apelin; apelinergic system; pathology of pregnancy; placenta; pregnancy.

Figure 1

Apelin isoforms derived from the 77-amino-acid pre-propeptide. Based on Chen et al., 2003 [7].

Figure 2

Role of apelin in reproductive and cardiovascular systems. MAPK3/1—mitogen-activated protein kinase 3/1; AMPKα—5’AMP-activated protein kinase; AKT—protein kinase B; VSMC—vascular smooth muscle cells; Gc—granulosa cells; E2—estradiol, P4—progesterone; ↑—increase; ↓—decrease.

Figure 3

Activation of different signaling pathways and affinity of apelin/ELABELA to APJ receptor. AKT—protein kinase B; AMPKα—5’AMP—activated protein kinase; ERK1/2—extracellular signal activated kinase 1/2; P70s6k—ribosomal protein S6 kinase beta—1; PKC—protein kinase C; ATP—adenosine triphosphate; AMP—adenosine monophosphate; Camp—cyclic adenosine monophosphate; PI3K—phosphoinositide 3-kinase; ↑—increase; ↓—decrease.

Figure 4

A simplified structure of the human placenta, taking into account the cross-section through the placental villi.

Figure 5

Signal molecular pathways of placental processes regulated by apelin. APJ—apelin receptor; ERK 1/2—extracellular signal activated kinase 1/2; AKT—protein kinase B, AMPK—5’AMP-activated protein kinase; PKA—protein kinase A; +/– —occurs/does not occur through; ns—no study.

Figure 6

Changes in serum and placental apelin levels, as well as its administration effect during pregnancy pathologies. PE—preeclampsia; IUGR—intra uterine growth restriction; GDM—gestational diabetes mellitus; ↑—increase; ↓—decrease; ns—no study.