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Endothelin (ET)-1 has been implicated in a diverse range of signalling events in a wide variety of target tissues. Given its potent vasoactive function and the prevalence of hypertension in pre-eclampsia, there has been extensive research on the role of ET-1 in this disorder. Indeed, ET-1 has been suggested to contribute to hypertension in pre-eclampsia. Recently, ET-1 has also been implicated in the induction of both oxidative stress and endoplasmic reticulum stress in pre-eclampsia; each of which has been proposed to contribute to many of the clinical manifestations of this disorder. ET-1 has been shown to activate key signalling molecules that lead to induction of these stress pathways. The use of ET-receptor antagonists could block oxidative and endoplasmic reticulum stress. Hence, further research into the role of ET-1 in pre-eclampsia may lead to the development of possible strategies to circumvent these stress pathways and the associated pathology that occurs in pre-eclampsia.
Endothelin (ET)-1 has been implicated in a diverse range of signalling events in a wide variety of target tissues. Given its potent vasoactive function and the prevalence of hypertension in pre-eclampsia, there has been extensive research on the role of ET-1 in this disorder. Indeed, ET-1 has been suggested to contribute to hypertension in pre-eclampsia. Recently, ET-1 has also been implicated in the induction of both oxidative stress and endoplasmic reticulum stress in pre-eclampsia, each of which has been proposed to contribute to many of the clinical manifestations of this disorder. ET-1 has been shown to activate key signalling molecules that lead to induction of these stress pathways. The use of ET-receptor antagonists could block oxidative and endoplasmic reticulum stress. Hence, further research into the role of ET-1 in pre-eclampsia may lead to the development of possible strategies to circumvent these stress pathways and the associated pathology that occurs in pre-eclampsia.
), affecting between 2% and 8% of all pregnancies worldwide. It is a human pregnancy-specific disorder that adversely affects maternal vascular function and fetal intrauterine growth. The condition can also predispose the offspring to increased risk of chronic diseases, such as diabetes, cardiovascular diseases and obesity in later life (
) and therefore poses a major public health problem. Most cases of pre-eclampsia have an onset near term, but approximately 10% of cases have an early onset before 34 weeks of gestation (
). Early-onset pre-eclampsia that requires preterm delivery has an underlying pathology that differs from, and is more severe than, that of late-onset pre-eclampsia (
It is now well established that one of the underlying factors in the pathophysiology of pre-eclampsia is deficient conversion of the uterine spiral arteries. The placenta is supplied by maternal spiral arteries, which undergo major modifications during pregnancy to accommodate the increase in uterine blood flow from 45 ml/min in the non-pregnant state to 750 ml/min at term (
). This process of modification occurs between 6 and 18 weeks of gestation, over which period the maternal spiral arteries supplying the placenta undergo physiological conversion, whereby they lose their smooth muscle and elastic coats and become transformed into dilated flaccid conduits (Figure 1).
Figure 1Schematic 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
Pre-eclampsia is associated with abnormal conversion of the maternal spiral arteries supplying the placenta and with subsequent placental malperfusion (
). The malperfusion is thought to result in placental oxidative stress and release of a complex mix of factors, including pro-inflammatory cytokines, apoptotic debris and angiogenic regulators into the maternal circulation (
). Endothelin (ET)-1 is another factor that is found to be elevated in pre-eclampsia compared with normal pregnancy. In plasma from healthy pregnant women, the concentration of ET-1 ranges from 5 to 10 pg/ml, whereas the concentration is 20–50 pg/ml in the presence of pre-eclampsia (
The endothelins constitute a family of vasoactive peptides that have key physiological functions in normal tissue, acting as modulators of the vascular tone, tissue differentiation, cell proliferation, development and hormone production (
). ET-1 exerts its effects by binding to the endothelin A (ETA) and endothelin B (ETB) receptors, two highly homologous cell-surface proteins that belong to the G-protein-coupled receptor superfamily (
). This review explores the diverse roles of ET-1 in pre-eclampsia. Since its discovery in 1988, the major work on ET-1 has been on its vasoactive function. However, more recently there has also been extensive research on its involvement in various biochemical pathways. This review will outline some of the most significant findings implicating ET-1 in the pathophysiology of pre-eclampsia.
Hypertension in pre-eclampsia
Pre-eclampsia is defined by the International Society for the Study of Hypertension in Pregnancy as gestational hypertension of at least 140/90 mmHg on two separate occasions ⩾4 h apart accompanied by significant proteinuria of at least 300 mg in a 24-hour collection of urine arising de novo after the 20th week of gestation (
). Maternal endothelial cell dysfunction is a key pathology that leads to many of the clinical manifestations of pre-eclampsia, including the symptoms of hypertension and proteinuria (
). Endothelial dysfunction is a systemic pathological state of the endothelium that is broadly defined as an imbalance between vasodilating and vasoconstricting substances produced by (or acting on) the endothelium (
Endothelial function and dysfunction. Part I: methodological issues for assessment in the different vascular beds: a statement by the Working Group on Endothelin and Endothelial Factors of the European Society of Hypertension.
ET-1 is a potent vasoactive peptide and, given its increased concentrations in pre-eclampsia, there has been extensive research on the role of ET-1 in the induction of hypertension in pre-eclampsia. Indeed, ET-1 is found to induce vasoconstriction via the ETA receptor, which has been shown to contribute to hypertension in pre-eclampsia. Antagonism of the ETA receptor has proved beneficial in numerous animal models of gestational hypertension and it remains an intriguing target for pharmacological intervention in pre-eclampsia (
Other causative agents of hypertension in pre-eclampsia include the anti-angiogenic protein soluble fms-like tyrosine kinase-1 (sFLT-1), inflammatory cytokines and agonistic angiotensin II type-1 receptor auto-antibodies. Each of these factors has been shown to induce hypertension experimentally through the production of ET-1 (
). It is proposed that these factors cause endothelial cell injury, which would reduce the synthesis of vasorelaxing agents and increase the production of vasoconstrictors. This provides a potential mechanism by which ET-1 concentrations are increased, which could then act via the ETA receptor to induce vasoconstriction resulting in hypertension.
Oxidative stress in pre-eclampsia
Oxidative stress plays an important role in the pathophysiology of pre-eclampsia. A role for placental oxidative stress is suggested by numerous studies that have found increased products of oxidative stress in pre-eclampsia compared with normal pregnant women (
). There is also some evidence that supplementation during pregnancy with l-arginine and antioxidant vitamins helps to reduce the incidence of pre-eclampsia, which was shown in a study on a population at high risk of the condition (
Effect of supplementation during pregnancy with L-arginine and antioxidant vitamins in medical food on preeclampsia in high-risk population: randomized controlled trial EDITORIAL COMMENT.
). Oxidative stress gives rise to a number of different factors, including pro-inflammatory cytokines, such as tumour necrosis factor α and interleukin 1β, and anti-angiogenic factors, such as sFLT-1 (
Nuclear factor-kappa B, p38, and stress-activated protein kinase mitogen-activated protein kinase signaling pathways regulate proinflammatory cytokines and apoptosis in human placental explants in response to oxidative stress: effects of antioxidant vitamins.
Secretion of tumor necrosis factor-alpha from human placental tissues induced by hypoxia-reoxygenation causes endothelial cell activation in vitro: a potential mediator of the inflammatory response in preeclampsia.
). The pro-inflammatory environment is thought to lead to maternal endothelial cell dysfunction, resulting in the syndrome of hypertension and proteinuria in pre-eclampsia (
has demonstrated that ET-1 plays a role in the induction of oxidative stress in pre-eclampsia. ET-1 treatment of human placental explants and JEG-3 cells (putative models of trophoblasts) was found to alter the balance between oxidant forces (increased malondialdehyde concentrations) and antioxidant forces (decreased glutathione and ascorbic acid) in favour of oxidation (
). Glutathione protects against damage induced by reactive oxygen species and is also involved in the detoxification of lipid peroxides, while ascorbic acid is also a component of the antioxidant system. Thus, the net effect of ET-1 in the study by
), which together with oxidative stress can help explain a broader range of the symptoms in this disorder.
The ER is a multifunctional organelle involved in the synthesis and packaging of membrane and secretory proteins. In addition, the ER also serves as a reservoir of calcium ions (Ca2+) (
). In the ER lumen, Ca2+ is buffered by calcium-binding proteins. Many of these proteins also serve as molecular chaperones involved in folding and quality control of ER proteins (
), and their functional activity alters with changes in Ca2+ concentration. Loss of Ca2+ homeostasis in the ER impairs the post-translational modification of proteins, triggering ER stress-response pathways. ET-1 has recently been shown to be a potential cause of ER stress in pre-eclampsia (
). ET-1 was shown to act through the ETB receptor to activate the PLC/IP3 pathway to induce Ca2+ release from the ER and thereby stimulate ER stress. The proposed pathway was confirmed using inhibitors acting at the different stages (Figure 2) and also by siRNA knockdown of the ETB receptor, all of which blocked the induction of ER stress by ET-1. Many of the molecules that ET-1 was shown to activate have also been found to be activated in other tissues and cell types but this was the first report of their activation by ET-1 in relation to the induction of ER stress. Given the presence and activation of these molecules in other tissue and indeed other disease states, including neurodegenerative diseases (
Endothelin-B receptors on suprachoroidal melanocytes mediate an endothelin-1-induced increase in the intracellular calcium concentration of rabbit ocular suprachoroidal tissue.
), broader implications for ET-1 induced ER stress are suggested over and above the effects in pregnancy.
Figure 2Potential 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
). This increase was shown in an experiment where exposure of placental explants to hypoxia/reoxygenation, a potent stimulus of oxidative stress, induced ET-1 expression and release by the placental syncytiotrophoblast. Hence, deficient conversion of the maternal spiral arteries supplying the placenta, which has been proposed to result in excessive spontaneous constriction of the arteries, thereby exposing the placenta to the low-grade repetitive ischaemia-reperfusion injury that causes oxidative stress (
), would be a potential cause of the increased ET-1 concentrations detected in pre-eclampsia. As discussed earlier, ET-1 is itself a potential source of oxidative stress in pre-eclampsia (
), which implies that the increased production of ET-1 under oxidative stress can act in a positive feedback loop to generate more oxidative stress and thus more ET-1 production.
ER stress together with oxidative stress can explain many of the symptoms of pre-eclampsia. ER stress initiates induction of the unfolded protein response (UPR), which is responsible for the activation of three integrated signalling pathways that act to restore ER homeostasis. The UPR (i) reduces the burden of new proteins entering the ER lumen through attenuation of translation, (ii) enhances the protein folding capacity by increasing ER chaperone proteins and folding enzymes, and (iii) promotes degradation of remaining unfolded or misfolded proteins through increased capacity of the cytosolic ubiquitin-proteasome system (
). The UPR is initiated by three ER-localized protein sensors: PERK (double-stranded RNA-dependent protein kinase-like ER kinase), IRE1α (inositol-requiring 1α) and ATF6 (activating transcription factor 6). If the UPR fails to restore ER homeostasis, then apoptosis is induced in order to protect the organism by eliminating the stressed cells that produce misfolded or malfunctioning proteins. Apoptosis is mediated via CHOP or the IRE1–TRAF2–ASK1 complex (
demonstrated that the UPR manifests as a graded response in activation of the signalling pathways consequent upon ER stress (Figure 3).
Figure 3Pathways 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.
). Activation of the PERK pathway leads to protein synthesis inhibition, which is proposed to contribute to the intrauterine growth restriction phenotype that is commonly associated with early-onset pre-eclampsia. ET-1 also up-regulates expression of ER chaperone proteins via the ATF6 pathway. The chaperone proteins are induced to allow the ER to cope with the increased load of unfolded or misfolded proteins that accumulate under conditions of ER stress. The ER produces reactive oxygen species as a by-product of protein folding, which can activate a pro-inflammatory response. In conjunction with oxidative stress, the pro-inflammatory environment induced is thought to lead to maternal endothelial cell dysfunction, which clinically manifests as hypertension and proteinuria in pre-eclampsia (
Figure 4Flow 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.
In conclusion, ET-1 is clearly a critical factor that is implicated in a diverse range of biochemical pathways that can lead to many of the clinical manifestations of pre-eclampsia. Further research into the mechanisms by which ET-1 is able to induce these stress pathways and evaluation of the inhibitors that circumvent this stress may lead to the development of potential therapies for pre-eclampsia.
Acknowledgements
The author thanks Graham Burton, Martin Johnson and the CTR for all the guidance and support received during his PhD. The author would also like to thank his family; special thanks to Kirti and Ashok Jain, Ira, Leela and T3LOs.
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Plasma malondialdehyde, superoxide dismutase, sE-selectin, fibronectin, endothelin-1 and nitric oxide levels in women with preeclampsia.
Eur. J. Obstet. Gynecol. Reprod. Biol.2004; 113: 21-25
Nuclear factor-kappa B, p38, and stress-activated protein kinase mitogen-activated protein kinase signaling pathways regulate proinflammatory cytokines and apoptosis in human placental explants in response to oxidative stress: effects of antioxidant vitamins.
Endothelial function and dysfunction. Part I: methodological issues for assessment in the different vascular beds: a statement by the Working Group on Endothelin and Endothelial Factors of the European Society of Hypertension.
Endothelin-B receptors on suprachoroidal melanocytes mediate an endothelin-1-induced increase in the intracellular calcium concentration of rabbit ocular suprachoroidal tissue.
Secretion of tumor necrosis factor-alpha from human placental tissues induced by hypoxia-reoxygenation causes endothelial cell activation in vitro: a potential mediator of the inflammatory response in preeclampsia.
Effect of supplementation during pregnancy with L-arginine and antioxidant vitamins in medical food on preeclampsia in high-risk population: randomized controlled trial EDITORIAL COMMENT.
Arjun Jain obtained a BSc in biochemistry from Imperial College London (2007). Having completed with a first class honours, he then moved to the University of Cambridge for an MPhil (2008). He stayed on in Cambridge for a PhD, working with Professor Graham Burton on the role of endothelin-1 in the induction of placental endoplasmic reticulum stress in pregnancy disorders, such as pre-eclampsia and intrauterine growth restriction. He is going to take up a position in Switzerland with Professor Christiane Albrecht to continue research on pregnancy disorders.
Arjun Jain obtained a BSc in biochemistry from Imperial College London (2007). Having completed with a first class honours, he then moved to the University of Cambridge for an MPhil (2008). He stayed on in Cambridge for a PhD, working with Professor Graham Burton on the role of endothelin-1 in the induction of placental endoplasmic reticulum stress in pregnancy disorders, such as pre-eclampsia and intrauterine growth restriction. He is going to take up a position in Switzerland with Professor Christiane Albrecht to continue research on pregnancy disorders.
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