Endothelin-1: a key pathological factor in pre-eclampsia? Arjun Jain  Reproductive BioMedicine Online  Volume 25, Issue 5, Pages 443-449 (November 2012) DOI: 10.1016/j.rbmo.2012.07.014 Copyright © 2012 Reproductive Healthcare Ltd. Terms and Conditions

Figure 1 Schematic representation of the placenta comparing the endometrial spiral arteries in uninvaded arteries (non-pregnant), normal pregnancy and pathological conditions of pregnancy, such as pre-eclampsia. The extent and depth of trophoblast invasion is less in pathological compared with normal pregnancy, which results in inadequate transformation of the spiral arteries in the former (reproduced from Moffett-King (2002)). Reproductive BioMedicine Online 2012 25, 443-449DOI: (10.1016/j.rbmo.2012.07.014) Copyright © 2012 Reproductive Healthcare Ltd. Terms and Conditions

Figure 2 Potential mechanism by which endothelin-1 (ET-1) induces ER stress in pathological pregnancies. ET-1 binding the ETB receptor (ETBR) activates phospholipase-C (PLC)-catalysed hydrolysis of phosphatidylinositol 4,5-bisphosphate (PIP2) to produce diacylglycerol (DAG) and inositol 1,4,5-triphosphate (IP3). IP3 binding the IP3 receptor (IP3R) stimulates Ca2+ release from the ER, which induces ER stress. BQ788, an ETB receptor antagonist, U73122, an inhibitor of PLC activation and Xestospongin-c, an IP3 receptor inhibitor, as well as siRNA knockdown (KD) of the ETB receptor, all block the induction of ER stress by ET-1 (reproduced from Jain et al. (2012)). Reproductive BioMedicine Online 2012 25, 443-449DOI: (10.1016/j.rbmo.2012.07.014) Copyright © 2012 Reproductive Healthcare Ltd. Terms and Conditions

Figure 3 Pathways activated upon induction of endoplasmic reticulum (ER) stress by endothelin-1 (ET-1). PERK (double-stranded RNA-dependent protein kinase-like ER kinase), ATF6 (activating transcription factor 6), IRE1α (inositol-requiring 1α) and CHOP (C/EBP homologous protein) or the IRE1–TRAF2–ASK1 complex are induced as part of a graded response. Reproductive BioMedicine Online 2012 25, 443-449DOI: (10.1016/j.rbmo.2012.07.014) Copyright © 2012 Reproductive Healthcare Ltd. Terms and Conditions

Figure 4 Flow diagram summarizing stress pathways induced by endothelin-1 (ET-1) and how these could lead to some of the symptoms associated with pre-eclampsia. ER=endoplasmic reticulum; IUGR=intrauterine growth restriction. Reproductive BioMedicine Online 2012 25, 443-449DOI: (10.1016/j.rbmo.2012.07.014) Copyright © 2012 Reproductive Healthcare Ltd. Terms and Conditions