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.
Introduction
Pre-eclampsia is a major cause of clinical morbidity and mortality in pregnant women and prenatal infants (Roberts and Hubel, 1999), 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 (Barker, 1997, Briana and Malamitsi-Puchner, 2009) 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 (Lain and Roberts, 2002). 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 (Moldenhauer et al., 2003).
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 (Burton et al., 2009). 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).
Pre-eclampsia is associated with abnormal conversion of the maternal spiral arteries supplying the placenta and with subsequent placental malperfusion (Khong et al., 1986, Meekins et al., 1994). 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 (Cindrova-Davies et al., 2007b). 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 (Fiore et al., 2005).
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 (Nelson et al., 2003). The family of endothelins comprises three isoforms, each of 21 amino acids (ET-1, ET-2, ET-3). ET-1 is the most abundant member of this family (Struck et al., 2005) and is synthesized and secreted by a diverse range of cells, including the syncytiotrophoblast of the placenta and endothelial cells (Malassine et al., 1993). 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 (Karet and Davenport, 1994). Upon binding to these receptors, ET-1 triggers signalling events in a wide variety of target tissues (Yanagisawa et al., 1988). 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.
Section snippets
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 (Harbison et al., 2009). Maternal endothelial cell dysfunction is a key pathology that leads to many of the clinical manifestations of pre-eclampsia, including the symptoms of
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 (Aydin et al., 2004, Gupta et al., 2009, Hubel, 1999, Takagi et al., 2004). There is also some evidence that supplementation during pregnancy with l-arginine and antioxidant vitamins helps to reduce the incidence of pre-eclampsia, which
Endoplasmic reticulum stress in pre-eclampsia
Recent evidence also implicates placental endoplasmic reticulum (ER) stress in the pathophysiology of pre-eclampsia (Yung et al., 2008), 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+) (Zhang and Kaufman, 2008). In the ER lumen, Ca2+ is buffered by
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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Elevated endothelin-1 (ET-1) has been implicated in several diseases including preeclampsia, where it causes the induction of hypertension, oxidative stress, endoplasmic reticulum stress, microvascular dysfunction and tissue damage in different organs. ET-traps are Fc-fusion proteins with a design based on the physiological receptors of ET-1. This paper discusses the potential use of ET-traps as a therapeutic for preeclampsia. ET-traps potently bind and sequester pathologically elevated ET-1 to significantly reduce different markers of pathology to non-disease levels with no toxicity.
In human placenta, ET-1 increased malondialdehyde (oxidant) and decreased glutathione, glutathione disulfide and ascorbic acid (antioxidants) [217]. ET-1-induced oxidative stress can act as a positive feedback loop to generate more ET-1 [216]. ET-1-induced imbalance between the oxidant and antioxidant forces in preeclampsia setting provides a potential target for therapeutic intervention.
Sex differences in redox signaling in the kidney present new challenges and opportunities for understanding the physiology and pathophysiology of the kidney. This review will focus on reactive oxygen species, immune-related signaling pathways and endothelin-1 as potential mediators of sex-differences in redox homeostasis in the kidney. Additionally, this review will highlight male-female differences in redox signaling in several major cardiovascular and renal disorders namely acute kidney injury, diabetic nephropathy, kidney stone disease and salt-sensitive hypertension. Furthermore, we will discuss the contribution of redox signaling in the pathogenesis of postmenopausal hypertension and preeclampsia.
For ischemic strokes reduce risk by 29% and 31%. Jain et al.5 hypoxia causes oxidative stress of the placenta and will release other factors, such as proinflammatory cytokines, apoptotic debris, and angiogenic regulators into the maternal circulation. Endothelin-1 is one of the factors found to increase in preeclampsia patients compared to a healthy pregnancy.
This study aimed to evaluate the effect of aspirin and pravastatin compared with aspirin on endothelin-1 levels, and the pregnancy outcome in pregnant women high risk for preeclampsia.
It was a randomized clinical trial (RCT) analysis with block permutation. The sample divided into two groups. Group A as control has given aspirin 80 mg and group B as an intervention group given aspirin 80 mg plus pravastatin 20 mg twice daily until 35 weeks gestation. Level of Endothelin-1 examined before and after treatment.
There no differences found in endothelin-1 levels before and after being treated with aspirin or aspirin and pravastatin, as well as in the umbilical artery resistance index, fetal biometry, and the development of the fetus in two groups was typical at 28–32 weeks’ gestation. Similarly, no differences found in fetal outcomes such as preterm birth, fetal growth retardation, and the incidence of preeclampsia between the two groups.
As a conclusion, the administration of pravastatin, together with aspirin is no more effective than aspirin in preventing preeclampsia, to pregnancy outcome and decreasing endothelin-1 levels. No congenital abnormalities reported.
In this paper are discussed reasons to suspect that measurements of serum endothelin levels in women with preeclampsia may not provide accurate estimations of the degree of systemic endothelin receptor activation and reasons to suspect that systemic endothelin receptor saturation studies should provide such estimations more accurately.
The treatment of pre-eclampsia is problematic and mainly aims to minimize the symptomatic complications of the disease [44]. Given that research has shown that ET-1 is a primary pathological factor in pre-eclampsia [4,45], ET-traps could be used as a novel therapy for pre-eclampsia. Previous research has shown that different ERAs have an efficacious effect on blocking different pathological processes that are implicated in pre-eclampsia [45–47].
There is substantial research on the vasoactive peptide endothelin (ET)-1 in physiology, as well as in pathology. In fact, pathologically elevated levels of ET-1 have been found in several disease states, such as various cardiovascular diseases, different cancers, some neurodegenerative disorders, as well as in diabetes. Here, we describe and discuss ET-1, its importance in different diseases, and the potential therapeutic effects of ET-traps in the treatment of these diseases. Previous in vitro and in vivo research (in the diabetes disease space) demonstrated that ET-traps potently and significantly prevent the induction of different markers of diabetes-related pathology. This included induction of extracellular matrix (ECM) proteins (collagen 4α1 and fibronectin), which are pathologically elevated in diabetes. The ET-traps prevented induction of these and brought a significant return to non-diabetic levels. We also discuss the merits of using ET-traps over the currently used endothelin receptor antagonists (ERAs) and previously used therapeutic antibodies.
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.
