Sobrevia Et Al RAP RSIngpost (Oct 31 12)

Research Signpost 37/661 (2), Fort P.O.
Trivandrum-695 023 Kerala, India
Review Article
Recent Res. Devel. Physiol., 6(2012): 105-158 ISBN: 978-81-308-0489-7
7. Fetoplacental vascular pathophysiology in preeclampsia

Sobrevia L1, Guzmn-Gutirrez E1, Westermeier F1, Salomn C1, Arroyo P1, Palacios E1,2, Bugueo K1,3, Santos M1, Diez de Medina C1, Gonzlez M4, Escudero C5, Salsoso R6, Mate A6, Vsquez CM6, Pardo F1 and Leiva A1
Cellular and Molecular Physiology Laboratory (CMPL), Division of Obstetrics and Gynaecology School of Medicine, Faculty of Medicine, Pontificia Universidad Catlica de Chile, P.O. Box 114-D Santiago, Chile; 2Pontificia Universidad Catlica de Valparaiso, Valparaso, Chile; 3Faculty of Health Sciences, Universidad de Antofagasta, Antofagasta, Chile; 4Vascular Physiology Laboratory Department of Physiology, Faculty of Biological Sciences, Universidad de Concepcin, Concepcin Chile; 5Vascular Physiology Laboratory, Department of Basic Sciences, Faculty of Sciences, Universidad del Bo-Bo, Chilln, Chile; 6Department of Physiology, Faculty of Pharmacy. Universidad de Sevilla Sevilla, Spain
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Abstract. Preeclampsia is a syndrome that affects a significant proportion of pregnant women worldwide. The several hypotheses proposed regarding the aetiology of preeclampsia highlight the possibility of a critical role played by the placenta and the multiple molecules released by this organ in the onset of the syndrome. Recent reports suggest that not only the placenta itself but also fetal circulating factors such as lipids, including cholesterol, and the endogenous purine nucleoside adenosine, via activation A2A adenosine receptors, are determinant in this syndrome. Alternatively, maternal pregestational obesity and obesity in pregnancy determines the appearance of preeclampsia, with leptin as a key factor in this phenomenon. In addition, maternal and fetal insulin resistance associated with maternal obesity in pregnancy
Correspondence/Reprint request: Prof. Luis Sobrevia, Cellular and Molecular Physiology Laboratory (CMPL) Division of Obstetrics and Gynaecology, School of Medicine, Pontificia Universidad Catlica de Chile, P.O. Box 114-D, Santiago, Chile. E-mail: [email protected]
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could result from differential expression of insulin receptor isoforms A and B. Fetoplacental endothelium is a primary target for the action of these factors resulting in endothelial dysfunction. Thus, reduced synthesis and release of nitric oxide and increased plasma levels of adenosine are mechanisms involved in the genesis of preeclampsia. We here summarize these observations and propose potential links between these factors in the aetiology of this syndrome. We highlight the possibility that the placenta and the developing fetus are key elements leading to the onset of preeclampsia. Therapies could include modulation of the serum level of adenosine, cholesterol, insulin, and expression of adenosine and insulin receptors, as well as membrane transporters of nucleosides and cholesterol.
1. Introduction
A large number (~15%) of the women who become pregnant will develop complications leading to maternal or fetal vital risk. One of the perinatal diseases with significant impact is preeclampsia (PE) whose incidence varies between 2-15% in people from developed and undeveloped countries. The aetiology of PE is multiple, and, unfortunately, a significant number of cases are idiopathic, with no clear cause. Placental dysfunction in PE is a common condition also for several other diseases of pregnancy, where altered placental function associates with vascular and endothelial dysfunction, and/or a local environment limiting oxygenation to the developing fetus. However, there is no information addressing the mechanisms, and whether those leading to endothelial dysfunction are transversal for placental vascular dysfunction in terms of its macro and microcirculation. The normal development of the placenta is essential to maintain an adequate fetal development and growth. The human fetoplacental circulation under physiological conditions exhibits a high blood flow and reduced vascular resistance. Since the placenta lacks autonomic innervation, circulating, and locally released vasoactive molecules, such as nitric oxide (NO) or adenosine, are essential to maintain control of the fetoplacental haemodynamic. An alteration in this process, where the placental function is abnormal, referred as placental dysfunction, leads to different clinical manifestations, leading to a vast amount of clinical possibilities, maternal and/or fetal symptoms, as well as different short- and long-term prognosis.
2. Preeclampsia
Preeclampsia is a syndrome presented in human pregnancies since the 20th week of gestation, clinically characterized by hypertension and proteinuria (Brown et al., 2001; WHO, 2011a). Thus, PE could be mild
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(proteinuria 3 g/24 hours, blood pressure 140/90 mmHg) or severe (proteinuria 5 g/24 hours, blood pressure 160/110 mmHg) (Geller et al., 2004). A recent classification includes the gestational age at which this syndrome appears to be PE of early-onset (<34 weeks of gestation (wg)) or late-onset (>34 wg) (Fugelseth et al., 2011). PE is a leading cause of maternal and infant morbidity and mortality related with a high risk (2 to 4 fold) for stillbirth, growth restriction and preterm births (Xiong et al., 2002a; Villar et al., 2006; Duley, 2009). The risk of maternal death due to severe PE is four times greater if the diagnose is done before the 32 wg, and most of these deaths result from complications such as brain haemorrhage, kidney or liver failure (Xiong et al., 2002b; Duley et al., 2006; Duley, 2009; Young et al., 2010). A commonly accepted treatment of this syndrome is the interruption of pregnancy if it develops after 34 wg. However, the benefits of this action must be considered together with the likelihood of fetal immaturity. There are certain risk factors that predispose to the occurrence of PE. These factors relate mainly to the pre-existence of endothelial injury or chronic inflammation, especially in essential hypertension, diabetes mellitus and chronic kidney damage. Also, a history of severe PE or eclampsia in previous pregnancies confers an increased risk for future pregnancy (Sibai et al., 2005; Backes et al, 2011). It is generally agreed that PE results from the existence of trophoblasts, which form the syncytiotrophoblast in direct contact with maternal blood (OSullivan et al., 1982; Myatt, 2010). From a clinical point of view, it is widely accepted that the development of PE during pregnancy requires the presence of the placenta, as the clinical pictures of the syndrome will not appear if this organ is not present and disappears after childbirth. Moreover, the presence of the fetus for the development of this condition is not necessary because it can happen in a hydatidiform mole (Page, 1939). The pathophysiological mechanism associated with this phenomenon involves a failure in the placentation that precedes the characteristic clinical manifestation of the syndrome (Burton et al., 2009a; Roberts & Rajakumar, 2009; Roberts & Escudero, 2012). The physiological placentation process involves at least two stages: the first, where predominates cytotrophoblast exhibiting a proliferative phenotype until the 12th wg, characterized by a relative hypoxia; and the second beginning at 12th wg and that will change the proliferative cytotrophoblast of the villi core towards an invasive phenotype (extravillious trophoblasts) which is mediated by changes in the concentration of oxygen (O2) in the intervillious space (Casanello & Sobrevia, 2010). The hypothesis widely accepted for the pathophysiology of PE indicates the following events: an impaired cytothophoblasts transformation toward extravillous
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trophoblasts resulting in a narrow invasion into the maternal vascular bed (Genbacev et al., 1997; Red-Horse et al., 2004). This phenomenon leads to a reduced trophoblasts invasion into maternal spiral vessels preventing its transformation into capacitance vessels. This will compromise the maternal blood flow towards the placenta, which in turn would trigger an ischemiareperfusion phenomenon associated to high perfusion pressure generating a continues shear stress against the placenta and on syncytiotrophoblasts (the cell layer in direct contact with maternal blood) (Burton et al., 2009a). These phenomena trigger cell damage (i.e., necrosis) leading to detachment and release of cell fragments (microparticles or nanoparticles) towards maternal circulation (Burton & Jones 2009). Within these microparticles harmful elements (such as phospholipids with an altered biochemistry, free radicals, purines) will be transported affecting the maternal endothelium. These elements will be responsible for triggering an exacerbated inflammatory response, endothelial dysfunction, vasoconstriction (hypertension) and glomerular endotheliosis (proteinuria). At the same time, these changes would generate a vicious cycle that will chronically affect the placental blood flow and maternal endothelial function (Roberts & Rajakumar, 2009; Roberts & Escudero, 2012). In addition, even when the mechanisms involved in these alterations are still unknown it has been proposed that an impaired maternal immune recognition associates with increased expression of the hypoxia inducible factor 1 (HIF-1), transforming growth factor 3 (TGF-3) and the vascular endothelial growth factor 1 (sFlt1, soluble fmslike tyrosine kinase 1), but decreased PlGF and NO (Casanello & Sobrevia, 2010; Escudero et al., 2008). Nevertheless the actual evidences suggest that in severe PE a reduction in placental angiogenesis could also be a mechanism responsible for the observed reduced placental blood flow, while in mild PE the observed normal blood flow could result from either not alterations or increased placental angiogenesis, and/or reduced vessel resistance. However, despite all this information, cellular mechanisms involved in the syndrome are not well understood (Ahmad & Ahmed, 2004; Escudero et al., 2008; Roberts & Escudero, 2012). An altered NO synthesis and plasma membrane transport mechanisms (amino acids and nucleosides transport) in human placental cells including the endothelium have been reported in PE (Weiner et al., 1994); as well as with an increased level of the soluble receptor for vascular endothelial growth factor 1 (sFlt1, soluble fms-like tyrosine kinase 1) (Levine et al., 2004). The proposed mechanism is that sFlt1 will binds vascular endothelial growth factor (VEGF) and placental growth factor (PlGF) depriving the endothelium of these essential survival proteins (Escudero & Sobrevia, 2008) and reducing NO synthesis (Ahmad et al., 2011).
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In parallel with the characterization of the intrinsic cellular mechanisms explaining the aetiology of PE, numerous methods have been used to predict the onset of PE with varying degrees of efficiency. Among them altered blood pressure, uric acid level and Doppler of the uterine arteries are considered risk factors (Monte, 2011). It has been possible to separate makers at the plasma or serum in early, intermediate and late stages of the syndrome (Sidani & Siddik-Sayyid, 2011; Monte, 2011). Early factors (assessed in the second trimester of pregnancy) are responsible for migration/inadequate trophoblastic invasion, including placental hypoxia and oxidative stress (i.e., leptin, uric acid, ascorbic acid, placental growth factor (PlGF)) and alteration of placentation (plasminogen activator inhibitor type 2 (PAI-2) antigen, PAI-1/PAI-2, vascular cell adhesion molecule (VCAM), intercellular adhesion molecule (ICAM) and inhibin. As described, the intermediate factors appear in the maternal circulation as a result of decreased placental perfusion and endothelial activation. These factors are present in the maternal plasma or serum before the onset of clinical signs of the disease and are associated with placental deficit (transforming growth factor 1 (TGF-1) and SS3 (TGF-SS3), PAI-1, PAI-2) and in the response of the placenta to hypoxia or oxidative stress (leptin, endothelin-1, asymmetric dimethyl arginine (ADMA), malonyldialdehyde (MDA), F2isoprostano, nitrotyrosine, homocisteinemia, vitamin B12, folic acid, VEGF, PlGF, uric acid). The late factors appear as a result of the activation of the endothelium or in a state of endothelial dysfunction including those associated with vasoconstriction (neurokinin-B, neuropeptide Y, endothelin 1 (ET-1), ADMA), compensation by vasoconstriction (NO release), impaired endothelial function (VEGF, IL-12, IL-6, tumour necrosis factor (TNF), VCAM-1) and impaired renal function (uric acid). While these markers in general have not increased the predictor capacity of the Doppler of the uterine artery in the second trimester of pregnancy, some of these, especially those related to antiangiogenesis such as sFlt1, PlGF and Seng, precede the onset of the signs of PE in at 5 to 8 weeks. However, despite that, it would be extremely useful to have predictive markers of PE within the first trimester of pregnancy in order to design appropriate prevention strategies (Monte, 2011).
2.1. The fetus in preeclampsia

It is well known that PE has a substantial impact on the intrauterine environment leading to fetal and neonatal morbidity and mortality. Thus, in a study conducted by the World Health Organization (Villar et al., 2001), it has been shown that the rate of preterm delivery was higher in newborns
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from PE compared with newborns from normal pregnancies (Villar et al., 2006). Moreover, diagnosis of intrauterine growth restriction (IUGR) is more often associated to PE compared to idiopathic IUGR (Sibai et al., 2005; Villar et al., 2006; Bertoglia, 2010). Thus, offspring from PE, principally those exposed to severe PE, usually exhibit prematurity (below 37 wg) or severe prematurity (below 27 wg), low birth weight and consequently high risk for stillbirth or perinatal death (Sibai et al., 2005). In fact, the fetal and neonatal mortality in PE resulted to be ~2.2 and 2.4%, respectively (Villar et al., 2006). High infant morbidity and mortality associated with PE is associated to prematurity or IUGR. However, cerebral palsy risk is markedly increased in infants born preterm or in those children born with low weight (Argyropoulou, 2010) whereas babies from PE (mainly severe PE) have a lower risk for cerebral palsy (Xiong et al., 2002b). Additionally in preterm newborns from severe PE exhibit elevated systemic blood pressure compared to preterm newborns from normal pregnancies (Swarup et al., 2005). PE has been also associated with the presence of febrile seizures (Vestergaard et al., 2003) or transient hearing defects (Bakhshaee et al., 2008). In a prospective cohort study of 324 preterm neonates with birth weight 1500 g and gestational age 32 weeks, PE was associated with by 60% reduction in the risk of retinopathy associated to prematurity and by 60% in the severe retinopathy cases (Fortes et al., 2011). Thus, it is intriguing that PE could be associated with fetal morbidity and in some cases with fetal protection against defect observed in premature babies. Therefore, fetal adaptation to PE might generate a particular phenotype different from premature or growth restricted babies.
2.2. The placenta in preeclampsia

The placenta has long been recognized as the necessary component for the genesis of PE. Initial evidences show that PE is present in cases of hydatidiform moles with abundant trophoblasts but no the fetus (Page, 1939), or the development of this disease in cases of abdominal pregnancies where placenta is implanted outside the uterus and the resolution of PE is delayed as long as the placenta is reabsorbed (Shembrey & Noble, 1995) or the disappearance of the disease after the placenta extraction in normal deliveries of caesarean sections (Sibai et al., 2005). Nowadays, there are several evidences linking reduced placental perfusion associated with PE development (Roberts & Gammill 2005; Escudero et al., 2009a; Roberts & Escudero 2012). The causes for the reduced placental perfusion in PE could be due to preplacental factors, where the reduced blood flow towards the
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placenta results from preservation in the capacity of contraction of the spiral arteries offering high resistance and intense pressure against the placenta (Burton et al., 2009b). Another cause could be placental factors, characterized by a failure in the process where endothelium and smooth muscle cells in the maternal spiral arteries must be replaced by invasive syncytiotrophoblast, allowing the transformation of the maternal vessels into a capacitance phenotype, reduced placental perfusion due to reduced placental angiogenesis especially in severe PE, or the presence of large placentas with a relative hypoperfusion (i.e., hydatidiform moles, multiple gestations). Furthermore, combined preplacental and placental factors could also be the cause, a condition that is, in fact, the most common in PE.
3. Vascular dysfunction in preeclampsia

The greatest risk of fetal morbidity and mortality in PE might be associated to a reduction in placental blood flow (Di Paolo et al., 2003; Kofinas et al., 2007), leading to limited fetal access to nutrients that eventually will affect its development. The causes for the decrease in blood flow to the placenta in pregnancies with PE are not entirely clear, but might be associated with maternal and placental vascular dysfunction (Escudero & Sobrevia, 2008, Escudero et al., 2009a; Roberts & Escudero, 2012).
3.1. Regulation of placental vascular tone in preeclampsia

The regulation of vascular tone in the placenta depends on its capacity of synthesis and reactivity to local and circulating vasoconstrictors and vasodilators (King et al., 1995, Webster et al., 2008; Casanello et al., 2007; Escudero & Sobrevia, 2008; Sobrevia & Casanello, 2010; Roberts & Escudero, 2012). The analysis of the information derived from echography show an increased index of uterine artery pulsatility (Di Paolo et al., 2003) and higher hypoechoic areas (Kofinas et al., 2007) in the placenta from PE suggesting reduced in the uterine artery and placenta blood flow, respectively. Moreover, there is no significant difference in the index of umbilical artery pulsatility in PE compared with normal pregnancies (Luzi et al., 1999). Thus, it is suggested that PE was associated with alterations in placental and fetal blood flow probably due to its redistribution in the placenta. A reduction in the placental blood flow associates with increased sensitivity of placental vasculature to vasoconstrictors such as angiotensin II, ET-1 and ET-3, prostaglandin F2 (PGF2), PGE2 and PGD2, as well as
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thromboxane A2 is reported in PE (Walters et al., 1991; Ajne et al., 2005). Similarly, even when the fetoplacental vasculature is highly sensitive to vasodilators such as prostacyclin (PGI2) and NO (Walters et al., 1991, King et al., 1995), several studies report that in PE the feto-placental tissue show reduced synthesis, less biological effect and/or diminished bioavailability of NO (Escudero & Sobrevia, 2008; Escudero et al., 2009a,b; Myatt 2002, 2010; Veas et al., 2011). It now clearer that synthesis and activity of NO depends on the placenta cell type where it is investigated. For instance, in a cross sectional study it is shown that human umbilical vein endothelial cells (HUVEC) isolated from mild and severe PE exhibit low capacity of histamine-stimulated NO synthesis compared with cells from normal pregnancies (Veas et al., 2011). This phenomenon was negatively correlated with maternal serum levels of VCAM-1 and sFlt1. Therefore, severe PE is characterized by high maternal level of soluble VCAM-1 and Flt1 associated with decreased production of NO in the fetal endothelium. Adenosine is a modulator of placental vascular tone with a differential effect on chorionic and umbilical vessels (Donoso et al., 2005; Westermeier et al., 2011; Leiva et al., 2011; Pardo et al., 2012). A higher expression of adenosine receptors (ARs) in placental homogenate have been reported in PE (von Versen-Hynck et al., 2009), but reduced expression of A2A adenosine receptor (A2AAR) without changes in A2BAR, in primary culture of human placental microvascular endothelial cells (hPMEC) was shown (Escudero et al., 2008). In addition, it has been suggested that adenosine increases NO synthesis in HUVEC (Vsquez G, 2003; Vsquez et al., 2004) and hPMEC (Escudero et al., 2008) by activation of adenosine A2A adenosine receptors (A2AAR), suggesting a role for adenosine as a vasodilator in the human fetoplacental vasculature (Sobrevia et al., 1996; Sobrevia & Mann, 1997; Wyatt et al., 2002; Sobrevia & San Martn, 2006; Escudero et al., 2008; Sobrevia et al., 2011; Westermeier et al., 2009, 2011; Guzmn-Gutirrez et al., 2011; Leiva et al., 2011; Pardo et al., 2012). However, the activation of another group of adenosine receptors, i.e., A2BAR, increases the synthesis of thromboxane and causes vasoconstriction in chorionic vessels (Donoso et al., 2005). The physiological significance of these findings in umbilical and chorionic vessels is not well understood, but might be related to the mechanisms of redistribution of blood flow to areas with low partial O2 pressure (PO2) as found in other tissues such as the lung (Gottlieb et al., 1984). These differential events (i.e., vasodilation or vasoconstriction depending on the vascular bed) are of great importance in pathological conditions associated with decreased blood supply as in the placenta of pregnancies with PE (Di Paolo et al., 2003; Kofinas et al., 2007).
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3.2. Preeclampsia and intrauterine growth restriction

The current evidence suggests that PE is a maternal condition that also affects the developing fetus in a defined group of patients (~30% of pregnant women with PE have children with IUGR). However, other pregnancies with PE (~70%) undergo a normal fetal development. Since placentation a continuous and growing release of trophoblastic material (including the fetal DNA) to the maternal circulation occurs. The first pathophysiological stage of the disease is hard to diagnose, but the second one is the clinical syndrome itself. Similarly, uterine artery Doppler allows the study of PE and IUGR in unselected populations with high variability. This is due to the variability in gestational age at the time of the patient examination as well as methodology and definitions of poor perinatal outcomes. Harrington and colleagues (1997) found that 4% of pregnant women showed increased resistance of uterine arteries at 24 wg with 55 and 30% of pregnant women developing PE and IUGR, respectively. However, when adverse perinatal outcome was defined as PE or IUGR before the 34 wg an abnormal Doppler increased the sensibility to 90 and 60%, respectively. In a metaanalysis including 27 studies and 12.994 pregnant women, where uterine artery Doppler was used as predictor of IUGR and PE, it was concluded that Doppler has a moderate skill in predicting these pathologies. However an abnormal Doppler in the second trimester of pregnancy increases the risk of PE by 6 fold, making it clinically relevant to the mother. The usefulness of uterine artery Doppler in the first trimester of pregnancy is of less impact than in the second trimester. It has been shown that a pulsatility index on the 95 percentile at 12 wg predicts 60% of severe PE and 30% of severe IUGR (defined as those pregnancies that were interrupted prior the 32 wg). On the other hand, patients with PE have uterine arteries pulsatility index that increased significantly at 12 wg compared with controls (Parra et al., 2001). In addition, its ability to predict severe PE (defined as those pregnancies interrupted before the 35 wg) was higher in 40%. Despite the development of PE in the mother, in the fetus and possibly also in the placenta, several mechanisms helping to ensure the normal growth of the developing fetus are likely triggered. Although the specific mechanisms are still unknown, it has been proposed that in PE and IUGR there is a reduction in the formation of placental blood vessels or an increase in placental vasoconstriction, given for example by a reduction in the synthesis of vasodilators such as NO (Table 1) (Webster et al., 2008; Bernardi et al., 2008, Roberts & Hubel, 2009). Thus, the relative reduction in utero-placental blood flow, secondary to alterations in placentation, could be, in fact, what ultimately leads to the development of these pathologies.
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Table 1. Alterations in preeclampsia coursing with or without intrauterine growth restriction.
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This is evidenced by histopathological changes in the placental implantation site where 80-100% of patients with PE and ~75% of patients with IUGR have a deficit in the extravillous trophoblast invasion into maternal spiral arteries. It is fairly agreed that the sequence of events leading to the development of PE and/or IUGR may be explained by a first stage of defective trophoblastic invasion, which occurs early in pregnancy and leads a state of high resistance of the utero-placental circulation, detected by an increase in resistance of the uterine arteries. In addition, the persistence of a state of reduced infusion leads to placental hypoxia, which will increase the local oxidative stress. This phenomenon will affect the growth of the fetus, but if these alterations happen in almost all cases of IUGR and PE, a question that remains unanswered is how the same pathophysiological processes trigger different clinical maternal conditions? One of the possibilities is that PE is mainly associated with the release of syncytiotrophoblast microparticles (STBM) (Goswami et al., 2006). This study showed that women with PE exhibit higher level (~2 fold) of STBM than normal pregnancies (matched by gestational age). However, the STBM level was similar between IUGR pregnancies compared with normal pregnancies. These results were further confirmed by others groups (Germain et al., 2007; Than et al., 2008) suggesting that depending on the quantity of STBM released into the maternal circulation a different pathophysiological process leading to PE or IUGR could account.
4. Adenosine in the placenta from preeclampsia

Adenosine is an endogenous purine nucleoside that maintains the homeostatic equilibrium via activation of adenosine receptors (ARs) (Schiemann et al., 1990). Adenosine biological effects include modulation of energy homeostasis (ATP metabolism), regulation of vascular tone (Vazquez et al., 2004; Westermeier et al., 2011), angiogenesis (Feoktistov et al., 2002, 2004, 2011), proliferation (Grant et al., 2001), endothelial permeability (Richard et al., 1998), inflammation (Olah et al., 2000), and protection against oxidative stress (Yang et al., 2005). Preeclampsia also associates with increased plasma adenosine concentration with the subsequent alterations of specific endothelial cell functions such as angiogenesis and endothelial cell proliferation (Escudero et al., 2009a) (Figure 1). Several reports show that adenosine plasma level in the fetal and maternal blood in PE is higher compared with normal pregnancies (Yoneyama et al., 1996, 2002). Adenosine plasma level in umbilical blood samples from PE without
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Figure 1. Adenosine effect in human placenta endothelial cell function in preeclampsia. Adenosine fetal plasma concentration is increased in preeclampsia thus activating adenosine receptors subtypes A1, A2A, A2B and A3 in the human placental tissue. Changes in adenosine receptor expression caused by or associated with preeclampsia could lead to a defective signalling resulting in altered function of the endothelial cells causing for example abnormal angiogenesis and cell proliferation in the human placenta (Escudero et al., 2008; von Versen-Hynck et al., 2009.
fetal hypoxia was reported as ~600 nM (Yoneyama et al., 1996), a concentration similar to that found in human umbilical blood in normal pregnancies (Maguire et al., 1998), whereas this level of adenosine increased by ~3 fold (i.e., ~1800 nM) in PE coursing with fetal hypoxia. Similarly, high plasma levels of adenosine have been reported in the maternal blood in PE (~680 nM) compared with normal pregnancies (~390 nM) (Yoneyama et al., 2002). A significant positive correlation between increased adenosine plasma level and PE severity has been proposed (Yoneyama et al., 2002). Only few studies show that adenosine deaminase (ADA) activity is, in fact, increased in maternal and umbilical vein whole blood and in placental tissue from women with mild or severe PE (Kafkafsli et al., 2006). This study established that increased ADA activity was related to the presence of the
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disease but not to the severity of patients clinical symptoms. In addition, ADA activity, and possibly the isotype 2 of ADA (ADA2) (Yoneyama et al., 2002), was also found increased in maternal and umbilical cord whole blood. This finding was proposed as a marker of immunological disorders that could potentially be related to the pathogenesis of PE. In addition, increased ADA activity could be an adaptive response of the fetoplacental vasculature to PE intending to reduce the elevated adenosine plasma levels detected in the maternal and fetal blood in this syndrome.
4.1. Adenosine receptors and preeclampsia

Four subtypes of ARs have been identified, i.e., A1AR, A2AAR, A2BAR and A3AR. These subtypes exhibit different pharmacological properties, and are expressed in different tissues with different order of potency of ligand binding and cell signalling associated mechanisms (Ralevic & Burnstock, 1998; Fredholm et al., 2011). These characteristics show that differential ARs expression is key in adenosine biological effects (Schulte & Fredholm, 2003; Eltzschig, 2009; Fredholm et al., 2011). Activation of A1AR and A3AR leads to inhibition of adenylyl cyclase and activation of phosphatidylinositol 3-kinase (PI3k)/Akt pathway, while A2AAR and A2BAR activates adenylyl cyclase (Eltzschig, 2009). In the placenta from PE higher ARs expression in syncytiotrophoblast, endothelium and myofibroblasts compared with normal pregnancies is found (von Versen-Hynck et al., 2009). However, in hPMEC, a cell type representative of fetoplacental microvascular endothelium (Sobrevia et al., 2011), it has been seen that only A2AAR expression is decreased when compared with hPMEC from normal pregnancies (Escudero et al., 2008). In HUVEC, a cell type representative of fetoplacental macrovascular endothelium (Sobrevia et al., 2011), the expression of A2AAR, A2BAR and A3AR, and a reduced but still detectable expression of A1AR are reported (Liu et al., 2002; Wyatt et al., 2002; Feoktistov et al., 2002). However, ARs expression in HUVEC from PE has not been studied (Escudero et al., 2008; Roberts & Escudero, 2012). Interestingly, it has been shown that expression and angiogenesis-associated to activation of A2BAR are upregulated in this cell type in response to hypoxia (Feoktistov et al., 2002; Eltzschig et al., 2003). A potential crosstalk between adenosine and other molecules (i.e., hormones, cytokines) have not been described in placental tissue from PE, suggesting that differential expression of ARs subtypes could contribute to understand functional heterogeneity of human placental vascular endothelial cells in PE (Sobrevia et al., 2011).
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4.2. Adenosine transporters and preeclampsia

Endothelial cells from placental tissue (i.e., HUVEC and hPMEC) maintain normal adenosine extracellular levels by an efficient uptake of this nucleoside (Escudero et al., 2008; Westermeier et al., 2011; Salomn et al., 2011), thus modulating its broad biological effects (Eltzschig, 2009). At present, nucleoside transport in human placental endothelial cells is mediated via the Na+-independent, human equilibrative nucleoside transporters (hENTs). Four members of the ENTs family of solute carriers (SLC29A genes) have been cloned from human tissues, i.e., hENT1, hENT2, hENT3 and hENT4 (Baldwin et al., 2004; Westermeier et al., 2009; Leiva et al., 2011). In HUVEC, adenosine transport is mainly (~80%) mediated by hENT1 (inhibited by <1 M nitrobenzylthioinosine, NBTI) with a remaining transport mediated by hENT2 (inhibited by >1 M NBTI) (Molina-Arcas et al., 2009; Westermeier et al., 2009). On the contrary hENT3 and hENT4 seems not to play a physiological role in endothelium (Westermeier et al., 2009; Leiva et al., 2011). hENT1 and hENT2 are also expressed in hPMEC; however, in this cell type these membrane transporters have a comparable relative contribution to the total adenosine transport (Escudero et al., 2008). We have shown that hPMEC isolated from pregnancies with PE exhibit reduced maximal velocity (Vmax) of hENT1-mediated adenosine transport, but increased Vmax for hENT2-mediated transport (Escudero et al., 2008). Since the apparent Km values were unaltered in PE, the relative effect of this pathological condition on the maximal transport capacity (Vmax/Km) mediated by hENT2 compared with cells from normal pregnancies was higher (~2 fold), but for hENT1 it was reduced (~75%). In addition, the relative contribution of hENT1 compared with hENT2 to total adenosine transport (i.e., hENT1 + hENT2) in hPMEC from normal pregnancies was higher (~7.9 fold) compared with cells from PE. Thus, even when adenosine transport in hPMEC from PE seems preferentially mediated by hENT2, this phenomenon might be insufficient to reverse the reduced hENT1-mediated transport seen in this syndrome. Moreover, high extracellular adenosine levels detected in HUVEC from pathological pregnancies (such as in gestational diabetes) (Westermeier et al., 2011) compared with cells normal pregnancies, leads to activation of adenosine receptors increasing the NO synthesis and membrane transport of the cationic amino acid L-arginine (Vsquez G, 2003; Vsquez et al., 2004), the substrate for NO synthesis via NO synthases (Moncada et al., 2006). The functional relationship between adenosine and L-arginine/NO pathway was first characterized and more recently referred as ALANO
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(Adenosine/L-Arginine/Nitric Oxide) signalling pathway in HUVEC (San Martn & Sobrevia, 2006; Leiva et al., 2011; Pardo et al., 2012). It was initially proposed that adenosine opens K+ channels, likely ATP-activated K+ channels (K+ATP) via activation of A2AAR in HUVEC, a possibility confirmed by observations showing an increase in the outward K+ current in response to adenosine in this cell type (Wyatt et al., 2002). Interestingly, this phenomenon was blocked by the NOS inhibitor NG-nitro-L-arginine methyl ester (L-NAME) and mimicked by the NO donors sodium nitroprusside (SNP) and S-nitroso-L-acetylpenicilamine (SNAP), suggesting that a NO-mediated membrane hyperpolarization may account for the stimulation of L-arginine transport in HUVEC challenged with adenosine. This pathway could be essential in diseases of pregnancies associated with fetal endothelial dysfunction such as PE where L-arginine transport via hCATs is reduced (Escudero, 2009; C Escudero, L Sobrevia, unpublished results).
5. Preeclampsia and obesity in pregnancy

5.1. Obesity
One of the major public health problems is obesity. This syndrome occurs with a misbalance between the energy intake and energy used accompanied with an over-storage of lipids in adipose tissue (Shoelson et al., 2007). Obesity contributes to the generation of the metabolic syndrome leading to alterations in several tissues triggering multiple systemic complications such as hypertension, dyslipidaemia and insulin resistance (Nishimura et al., 2009). According with the last World Health Organization report ~14% of the women suffer obesity (body mass index (BMI) >30) with ~20% with some level of overweight (BMI >25) (Heslehurst et al., 2007, 2010; Flegal et al., 2011; WHO, 2011b). The major effect of obesity is the manifestation of several metabolic alterations including endothelial dysfunction, which leads to hypertensive disorders (Tesauro & Cardillo, 2011). Worryingly, it is expected that obesity during pregnancy could becomes a condition altering fetal development and growth due to the abovementioned maternal obesity-associated metabolic changes. It is well documented that PE incidence associates with a higher BMI (Aliyu et al., 2010; Seabra et al., 2011; Chung et al., 2012; Yazdani et al., 2012; Mandal et al., 2011). Nevertheless, there is not a clear correlation between the increase in BMI with the severity of PE (Roberts et al., 2011; Sohlberg et al., 2012). These findings correspond well with the hypothesis of two subsets of PE, the earlyonset disease with a predominantly placental and genetic origin and the lateonset disease with a stronger metabolic origin (Sohlberg et al., 2012).
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Figure 2. Obesity as a factor to develop preeclampsia. Obesity in pregnancy is primarily related with mild preeclampsia most likely due to increased () in cytokines such as interleukin 6 (IL-6) and tumour necrosis factor (TNF) and free fatty acids. This phenomenon leads to oxidative stress increasing the incidence of this syndrome. Insulin resistance and increased leptin level could also promote placental dysfunction in preeclampsia. The severe preeclampsia results from lean pregnant women (lean pregnancy) and is more related to a placental origin with a large genetic background (Roberts et al., 2011; Tosun et al., 2011).
Some groups report that obesity correlates with PE through a state of dyslipidaemia and increased level of inflammatory cytokines; however, these alterations are also seen in lean pregnant women coursing with PE (ZalvalzaGmez et al., 2011). The type of fat accumulated during pregnancy and in the pregestational period seems crucial and correlates with a higher risk of developing insulin resistance, diabetes mellitus type 2 (DMT2) and cardiovascular disease (CVD) (Strasser et al., 2012). Roberts and colleagues (2011) proposed that lean women showing an increase in the weight gain during pregnancy could exhibit higher incidence of PE likely resulting from increased liquid retention in response to cytokines release in the placenta. In addition, an increase in the level of free fatty acids in obesity could be a factor leading to oxidative stress associated with PE (Dandona et al., 2005; Roberts et al., 2011).
5.2. Cytokines/interleukins and obesity in pregnancy

Several studies associate obesity with chronic inflammation since blood markers such us IL-6, TNF, adipokins (including leptin) and others are increased in patients suffering of this syndrome (Table 2) (Dandona et al.,
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2004; Dandona et al., 1998; Kern et al., 2001; Pradhan et al., 2001; Vozarova et al., 2001). The endothelium is the first cell line exposed to these cytokines (Fantuzzi, 2005; Meijer et al., 2011; Tilg & Moschen, 2006; Weisberg et al., 2003) leading to altered eNOS expression and activity, and reduced bioavailability of the vasodilator NO (Kim et al., 2008; Suwaidi et al., 2000; Yamamoto et al., 2010). IL-6 stimulates B-lymphocytes and regulates T-cell signalling processes in PE (Lamarca et al., 2011). In the placenta, IL-6 is also expressed in the trophoblasts (Kk et al., 2012), thus, since IL-6 level is elevated in PE both in the maternal (Amash et al., 2010, Tosun et al., 2010, Xie et al., 2011, Kalinderis et al., 2011) and the umbilical sera, and correlates with the severity of PE (Tosun et al., 2010; Kk et al., 2012; degrd et al., 2001), this cell type could play key roles in this syndrome. In addition, elevated IL-6 level in PE could be a key phenomenon promoting endothelial cell dysfunction, not only in the mother but also in the fetus (Loockwood et al., 2008) thus preconceiving an inflammatory state in the newborn from this syndrome. Increased IL-6 levels associates with an altered biological action of ET-1, characteristic of hypertension (Epstein et al., 2009). Since both IL-6and ET-1 maternal serum level are increased in PE (Taylor et al., 1990) this could be a phenomenon that contributes to the abnormal trophoblast invasion in this syndrome by increasing TNF- levels (Zhou et al., 2011). Even when IL-6 is increased in the maternal serum from obese pregnant women (Lager et al., 2011), there is no information regarding
Table 2. Maternal and umbilical cord level of cytokines in preeclampsia.
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whether obesity is a factor leading to an increase of IL-6 higher than what is seen in non-obese pregnant women coursing with PE. This phenomenon could result in an increased incidence rather than the severity of the syndrome. Elevated TNF maternal serum level has been correlated with severe PE (Tosun et al., 2010; Xie et al., 2011) and in a minor level with mild PE (Yoneyama et al., 2002; Canakci et al., 2007; Guven et al., 2009; Tosun et al., 2010; Alanbay et al., 2011; Vitoratos et al., 2010; Sharma et al., 2011). Nevertheless, there are not reports describing increased TNF level in the human umbilical serum from obese women with PE (Tosun et al., 2010). Other studies show that placental NFkB activation in PE may be due to elevated fetal serum level of TNF (Vaughan et al., 2012). This phenomenon could be the result of an increased release of this cytokine from the trophoblasts (Ma et al., 2011) rather than the syncytiotrophoblasts (Goksu et al., 2011), thus inhibiting trophoblasts integration with the endothelium (Xu et al., 2011; Chen et al., 2010). Even when obese pregnant women do not exhibit increased TNF serum level it is unclear whether a potential increase in the level of this cytokine in obesity in pregnancy is a cause or is a consequence of PE; however, obesity could accelerates the pathogenesis of PE.
5.3. Leptin and obesity in pregnancy

Leptin is primarily secreted by the white adipose tissue (Masuzaki et al., 1995), and is also secreted by the human placenta (Masuzaki et al., 1997). In obese patients leptin serum level is increased and patients develop leptin resistance exhibiting a lost of its biological functions in target cells. It is known that leptin level in the serum (Mise et al., 1998; Adali et al., 2009; Molvarec et al., 2011) and leptin placental content (Lepercq et al., 2003, Hoegh et al., 2010) in women with PE are increased compared with women coursing with normal pregnancies, but its biological role is not fully understood (Table 3). Controversially, only one study has reported leptin levels in the human umbilical serum in PE showing that there are not differences compared with normal pregnancies; however, a reduced level of this molecule in the maternal serum in PE compared with normal pregnancy was detected (Lam et al., 2001). On the contrary, in another study an increase of leptin level was detected in umbilical vein blood in PE (Vitoratos et al., 2001). These apparent discrepancies could result from recruitment of patients that exhibit different weights in pregnancy and by the fact that some of the studies were performed in patients with term pregnancies, an unusual characteristic for pregnancies with severe PE. In obese pregnant women maternal leptin level is increased (Fattah et al., 2011); however, nothing is
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Table 3. Maternal and umbilical cord leptin levels in preeclampsia.
reported regarding leptin level in the fetal serum in these pregnancies. Thus, we highlight the fact that is crucial to determine the consequences of leptin increase in the fetus from PE since this phenomenon could lead to endothelial dysfunction (Korda et al., 2008).
6. Insulin resistance and vascular dysfunction in preeclampsia

Insulin resistance is defined as the inability of a known quantity of exogenous or endogenous insulin to increase glucose uptake and its metabolism in an individual as much as it does in a normal population (Lebovitz, 2001). Interestingly, insulin resistance has also been reported in
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patients with PE (Scioscia et al., 2009); however, the underlying mechanisms by which insulin resistance is associated with PE and the subsequent vascular dysfunction remains unclear. Endothelial dysfunction has been demonstrated in vessels from women with PE (Chambers et al., 2001), an effect that has been demonstrated in studies in vivo that impaired endothelial function persists into the immediate postpartum period (Ramsay et al., 2003) or impaired insulin sensitivity persists at least for six months after delivery following a pregnancy coursing with PE compared with normal pregnancies (Kaaja et al., 1999; Sattar & Greer, 2002; D'Anna et al., 2006). Thus, insulin resistance and vascular dysfunction syndrome seems to be crucial as an adverse intrauterine environment that could leads to diseases in the adulthood (Barker, 2004).
6.1. Impaired insulin signalling

Insulin is involved in fetal growth (Hattersley & Tooke, 1999) and their metabolic and mitogenic effects (Belfiore et al., 2009) are mediated via two cell surface tyrosine kinase receptors (Ebina et al., 1985; Ullrich et al., 1985). The human insulin receptor (IR) is encoded by a single INSR gene (insulin receptor gene) located on chromosome 19 and composed of 22 exons. INSR codes for two protein isoforms differing by a 12-amino acids insertion in the hormone-binding domain of the receptor resulting from exon 11 alternative splicing (Ebina et al., 1985; Ullrich et al., 1985; Sen et al., 2009, 2010; Talukdar et al., 2011). The IR isoform lacking exon 11 (11) (called IR-A) binds both insulin and insulin-like growth factor-II (IGFII), whereas the isoform expressing the exon 11 (11+) (called IR-B) binds only insulin (Frasca et al., 1999). A lack of regulation of the alternative splicing of INSR may therefore have important consequences for insulin and IGFII sensitivity and responsiveness. In fact, the mechanism involved in the control of the IR-B/IR-A ratio is of critical importance for the understanding of the role of IR in different disease states, including cancer (Belfiore et al., 2011), myotonic dystrophy (Savkur et al., 2001; 2004), type 2 diabetes mellitus (Sesti et al., 2001) and gestational diabetes (Westermeier et al., 2011). Interestingly, the potentially role of insulin receptor isoforms in PE is not yet reported. Daz and colleagues (2005) have shown a lower affinity of placental IR in PE compared with normotensive pregnant women. Moreover, expression of IR and its signalling related proteins in trophoblast microvillous plasma membranes from PE and normal pregnancies was similar, although impaired signalling cascade activation was observed following incubation with insulin in preparations from PE. Insulin increased the tyrosine phosphorylation of IR
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in preparations from PE and normal pregnancies, but failed to induce tyrosine phosphorylation of insulin receptor substrate 1 (IRS-1), IR-2 and the p85 regulatory subunit of PI3K in PE (Kunjara et al., 2000). Other studies show that there was no difference in the phosphorylation state of Akt/protein kinase B (PKB) in the absence (Orcy et al., 2008) or in presence (Ferreira et al., 2011) of insulin in placentas from PE or normal pregnancies. However, a role for Akt/PKB signalling pathway in the pathophysiology of PE associated with insulin resistance cannot be ruled out. In other hands, P-type inositol phosphoglycan (P-IPG), a second messenger of insulin, enhances the metabolic effects of insulin and is associated with insulin resistance (Scioscia et al., 2009). In addition, the expression of P-IPG is higher in the placenta (Kunjara et al., 2000), the fetus (detected in umbilical cord blood and amniotic fluid) (Paine et al., 2006; Scioscia et al., 2006) and in the mother (detected in the urine) (Paine et al., 2006; Williams et al., 2007) in pregnancies coursing with PE, effects that were not extended to newborns from PE (Scioscia et al., 2012). The latter results may help to elucidate how these abnormal metabolic conditions inuence fetal growth in pregnancies with early or late onset of PE. In a recent study, 46 normotensive pregnant women and 43 pregnant women coursing with PE were included in a search for polymorphisms (Machorro-Lazo et al., 2009) in INS (insulin gene), INSR and the mutations Ala513Pro and Gly972Arg of IRS-1. The protein products of these genes form a functional complex in response to insulin (SnchezCorona et al., 2004). In this study polymorphisms in INS or INSR were not detected in PE, suggesting that these genes would not be related with insulin resistance in this syndrome (Machorro-Lazo et al., 2009). However, further studies are needed to elucidate the complex relationship between functional polymorphisms and PE.
6.2. Insulin and programming

Preeclampsia is a pathological condition with heritability of ~55% (Williams et al., 2011), which is contributed to by both maternal and fetal genes. It is feasible that some of the alterations in the risk of developing PE seen in the offspring from pregnancies coursing with this syndrome relate to share genetic factors between the mother and child. The modication of these pathways also appear to be induced specically by in utero exposure to the syndrome. The underlying programming of vascular function may relate to structural, hypoxic or epigenetic programming of endothelial development and pathophysiology in PE (Davis et al., 2012a). By the other hand PE correlates with changes in the metabolism and hormones that may lead to alterations in tissue and organ development later in life (Gluckman &
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Hanson, 2004). Epigenetic mechanisms may cause long-term functional and structural changes (Gluckman et al., 2005; Goldberg et al., 2007). To date, women who have had a pregnancy complicated by PE are more likely to have heart disease in later life, and studies from the Helsinki Birth Cohort show that the offspring from mothers with PE have an elevated risk for stroke (Kajantie et al., 2009). Meta-analysis of available blood pressure data indicates that children exposed to PE in utero exhibit a systolic blood pressure that varies between 2-3 mmHg higher during childhood and young adult life (Davis et al., 2012b). Fugelseth and colleagues (2011) studied whether an altered myocardial function assessed by tissue Doppler echocardiography could be detected at the age of 5-8 years in offspring from pregnancies coursing by PE. The results show that offspring from PE have smaller hearts, increased heart rate and late diastolic velocity at mitral valve compared with offspring from normal pregnancies. Thus, pregnancies complicated by PE could have a negative impact on the heart already at the age of 5-8 years. Therefore, a better understanding of the mechanisms behind these phenomena this will provide the basis for future novel strategies to prevent CVD associated with PE pregnancy.
7. Dyslipidaemia in preeclampsia
Increased triglycerides and low-density lipoprotein (LDL) levels, with a reduction in high-density lipoprotein (HDL) levels are typically described in PE. This abnormal lipid metabolism may not only be a manifestation of PE, but dyslipidaemia could also be involved in its pathogenesis and may play an essential role in PE development (Thadhani et al., 1999; Demirsi et al., 2011; Sep et al., 2011). Additionally, different risk factors to develop PE have been assayed. Between those, dyslipidaemia, including hypercholesterolemia and hypertriglyceridemia, have been characterized as risk factors (Lorentzen et al., 1995; Grtacos et al., 1996; Enquobahrie et al., 2004; Magnussen et al., 2007; Demirci et al., 2012). Longitudinal studies in have shown that increased levels of cholesterol and triglycerides before pregnancy or in early pregnancy associate with increased risk to develop PE (Table 4) (Thadhani et al., 1999; Demirsi et al., 2011; Sep et al., 2011). Even when normal pregnancy is associated with a physiological increase in the plasma level of triglycerides and cholesterol (Potter & Nestel, 1979; Montes et al., 1984; Leiva et al., 2011), PE is associated with an increase in the plasma level of these type of molecules that is higher than the physiological process, a phenomenon that perhaps intends to assure fetal growth (Potter & Nestel, 1979; Belo et al., 2002; Demirsi et al., 2011; Sep et al., 2011). This phenomenon
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Table 4. Triglyceride and cholesterol level in early pregnancy: relative risk to develop preeclampsia.
has been associated with the occurrence of endothelial dysfunction (Van Wijk et al., 2000; Escudero et al., 2008) and acute atherosis in the placenta (Harsem et al., 2007; Staff et al., 2010) from PE such as in other vascular beds exposed to this lipidic profile (Demirsi et al., 2011; Leiva et al., 2011).
7.1. Endothelial dysfunction and dyslipidaemia in preeclampsia

Several studies suggest that endothelial function and vascular reactivity in both maternal and fetal-placental vasculature are altered in PE. In this regard, expression of VCAM-1 (marker of vascular dysfunction) correlates directly with the plasma concentration of LDL in PE, but show no correlation with other lipids, suggesting that LDL cholesterol could be involved in the endothelial dysfunction exhibited in patients with PE (Hubel et al., 1998). Endothelium dependent relaxation of umbilical and placental vessels has been reported in PE (Wareing & Baker, 2004; Dong et al., 2005; Karadas et al., 2007). The response to calcitonin gene related peptide (CGRP), an endothelium dependent vasodilator, is reduced in umbilical vessels from PE and is associated with a reduced expression of its receptor (Dong et al., 2005). Interestingly, the response to CGRP is also reduced in umbilical vessels from pregnancies coursing with maternal supraphysiological hypercholesterolemia (MSPH) without PE or another recognized pregnancy disease such as GDM or IUGR (Leiva et al., 2011). This phenomenon has been associated with the increased development of fetal atherosclerosis (Napoli et al., 1997, 1999). Since MSPH leads to reduced endothelial-dependent vascular umbilical
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response (Leiva et al., 2011) and fetal complications in PE have been related with reduced fetoplacental blood flow (Wareing & Baker, 2004) it is hypothesized that high levels of cholesterol in pregnancies with PE could contribute, at least in part, to the observed placental endothelial dysfunction in patients coursing with this syndrome. Several in vitro studies suggest that LDL leads to endothelial dysfunction by several pathways in different vascular beds. LDL and oxidized LDL (oxLDL) leads to reduced NO synthesis by several mechanisms including reduced L-arginine uptake (Kikuta et al., 1998; Schwartz et al., 2007), eNOS expression and function (Liao et al., 1995, Jimenez et al., 2001), tetrahydrobiopterin (BH4) synthesis (Ozaki et al., 2002; Tang et al., 2005), but increased arginases expression and activity (Ryoo et al., 2006, 2008). The levels of cholesterol and particularly LDL and oxLDL are higher in PE, and even when the expression of the receptor for oxLDL (lectin-like oxidized low-density lipoprotein receptor 1, LOX-1) is induced in maternal and placental cells from PE (Sankaralingam et al., 2009; Zhang et al., 2009) the effect of LDL from women with PE on the L-arginine transport and NO synthesis (i.e., the L-arginine/NO signalling pathway) in placental endothelium have been not yet reported. In PE the expression of eNOS in unchanged or even increased (Barden et al., 1999; Wang et al., 2004; Kanter et al., 2010), an effect that could corresponds almost partially to a lipidic-dependent effect. This is supported by the findings showing that HUVEC from pregnancies coursing with MSPH, whose comparable cholesterol level (>280 mg/dl at birth) to those in PE (~290 mg/dl at birth) (Solomon et al., 1999; Catarino et al., 2008), exhibits reduced NO synthesis without changes in eNOS expression (Leiva et al., 2012a). Additionally, other studies have shown increased expression and activity of arginases (a group of enzymes that compete by the common substrate L-arginine with eNOS in HUVEC) (Prieto et al., 2011) in the maternal blood (Bernardi et al., 2008) and in HUVEC from normal pregnancies in response to serum from women with PE (Sankaralingam et al., 2009, 2010a,b). Thus, arginase would be upregulated within the fetal endothelium and could contribute to the PE-associated endothelial dysfunction. This increased endothelial arginase activity has been also reported in hypercholesterolemic mice (Ryoo et al., 2006, 2008) and in HUVEC from pregnancies coursing with MSPH (Leiva et al., 2012b).
7.2. Atherosclerosis and dyslipidaemia in preeclampsia

The link between endothelial dysfunction and the latter development of atherosclerosis is widely recognized, where high levels of cholesterol are the main factor involved in both phenomena. In PE the oxidation of LDL
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lipoproteins is increased along with a reduction in the antioxidant effect of HDL (Sarandol et al., 2004; Demir et al., 2011), thus promoting endothelial dysfunction and foam cell formation which contributes to the formation of atheroma in human placental vasculature (Staff et al., 2010). In this regards, PE is associated with the appearance of atheroma in the placental vasculature, especially in the maternal uterine spiral arteries. The histological evidence in these vessels demonstrates visible lipid deposition in the wall of the spiral arteries, a phenomenon known as acute atherosis, i.e., a phenomenon requiring shorten times than for the development of atherosclerosis (Lorentzen & Henriksen, 1998; Staff et al., 1999; Harsem et al., 2007; Staff et al., 2010). Lipids deposition and foam cells in the acute atherosis in placental vasculature of women with PE are similar to atherosclerotic lesions in adults, both displaying vessel wall necrosis and accumulation of subendothelial lipids-laden foam cells (a hallmark of oxLDL), vascular fibrosis and perivascular lymphocytic infiltration. Even when the precise mechanisms involved in placental atherosis or the direct link between high levels of cholesterol and placental atheroma in PE are unknown (Satff et al., 2010), it is feasible to hypothesize that hypercholesterolemia leading to endothelial dysfunction and altered L-arginine/NO signalling pathway may be involved in PE.
7.3. Dyslipidaemia in preeclampsia and fetal programming

Additionally to the effect reported in maternal and the fetoplacental vasculature, the effect of dyslipidaemia on PE affect directly the offspring. Newborns of mothers with PE have increased triglycerides and reduced blood level of HDL (Rodie et al., 2004; Catarino et al., 2008; Akcakus et al., 2010). The latter is a phenomenon related with a pro-atherogenic lipidic profile that could be related with the future development of cardiovascular disease in these children (Kajantie et al., 2009; Davis et al., 2012a,b). Indeed, neonates from mothers with PE present an increased thickness of the aortic intima-media thickness, a parameter useful to determine atherosclerosis risk (Akcakus et al., 2010). In this regard, experimental evidence demonstrate that in placental tissue from PE, the expression of the transporter of cholesterol ABCA1 is increased in the first 25-33 wg (Plosh et al., 2010) coinciding with the fetal period where a positive correlation between the maternal and fetal levels of cholesterol has been documented (Napoli et al., 1997). Thus, the higher expression of ABCA1 in the placenta could result in increased cholesterol efflux from the maternal circulation to the placental tissue and eventually reaching the growing fetus, a phenomenon which may have physiological consequences such as the above mentioned increased
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thickness of the aorta intima media in neonates from PE (Akcakus et al., 2010; Plosh et al., 2010).
7.4. Preeclampsia, hypercholesterolemia and insulin signalling

Even when in PE there is no evidence regarding expression and function of IR-A and IR-B, the dyslipidaemia coursing with this syndrome could be involved in the alterations of the activity of both type of receptors as reported in other pathologies of pregnancy such as GDM, where the signalling of insulin mediated by IR-A and IR-B is altered and related with endothelial dysfunction due, most likely, to altered adenosine transport (Westermeier et al., 2009, 2011). Interestingly, in different endothelial cell types, including bovine and mice aortic endothelial cells (Wang et al., 2006, 2011), insulin receptors are located in caveolae, a microdomain of the plasma membrane enriched in caveolin (Parpal et al., 2000; Saltiel & Pessin, 2003; Ishikawa et al., 2005). Additionally, it has been determined that deficiency of caveolin disrupts the insulin signalling in mice aortic endothelial cells by reduction of IR protein expression, IR translocation to membrane and insulin-stimulated Akt phosphorylation (Wang et al., 2011). Because high levels of cholesterol increase the expression of caveolin and alter the caveolae structure modulating the activity of proteins located in caveolae (Feron et al., 1999), such as eNOS (Feron et al., 1999, 2001) and hCAT-1 (McDonald et al., 1997), it is feasible that alterations in insulin signalling in pregnancies coursing with increased levels of cholesterol including PE, a phenomenon directly related with endothelial dysfunction (Gonzlez et al., 2004; Westermeier et al., 2011), could be found.
8. Free radicals in preeclampsia

Oxidative stress related with abnormal vascular reactivity has been considered a key stage in the aetiology of PE (Myatt & Webster, 2009). This state is described as in imbalance in the production of reactive oxygen species (ROS) and the scavenger ability of antioxidant defences of fetoplacental tissues (Myatt et al., 2000; Myatt & Cui, 2004). The origin of PE has not well established, but there is increased evidence demonstrating that there is a higher accumulation of ROS and reactive nitrogen species (RNS) in the fetoplacental vasculature and the trophoblast (Webster et al., 2006, 2008; Myatt & Webster, 2009). The sources of ROS in the placental tissues are NADPH oxidase, mitochondria, cytochrome P450, endoplasmic reticulum, uncoupled eNOS, xanthine oxidase (XO) (Burton & Janiaux,
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2011). The main ROS involved in PE are superoxide (O2-), hydroxyl ion (OH-), hydrogen peroxide (H2O2), nitric oxide (NO) and peroxinitrite (ONOO-) (Burton & Janiaux, 2011; Gonzlez et al., 2011). In vascular cells of umbilical and placental tissues, the concomitant increase in the synthesis of NO and O2- results in higher levels of ONOO-, a very deleterious ROS that causes protein nitration and alters protein activity. The reaction leading to formation of ONOO- is kinetically favoured because it is higher than the reaction of NO with the soluble guanilyl cyclase (sGC) or O2- with superoxide dismutase (SOD) (Webster & Myatt, 2008). For these reasons stimuli for example, high extracellular D-glucose) causing increase of NO and ROS synthesis in endothelium do not result in relaxation of smooth muscle cells, but in endothelial dysfunction, thus triggering of vascular diseases (Sobrevia & Gonzlez, 2009). In animal models the reduction of uteroplacental blood flow causes hypertension, characteristic of PE (Myatt & Webster, 2009). The reduction of uteroplacental blood flow could be focused in alterations of vascular reactive of placental and umbilical vessels, alterations with an origin in early stages of placentation resulting in reduced blood flow to the fetus and increased placental sensitivity to vasoconstrictors. In placental tissue from normal pregnancies it has been demonstrate that acute exposure of xanthine/xanthine oxidase or hydrogen peroxide (H2O2) increases the contractility of human chorionic arteries, an effect abolished by catalase, an enzyme that catalyses the conversion of H2O2 into water and O2- (Mills et al., 2009). Administration of ONOO- caused relaxation in chorionic arteries preconstricted with analogues of thromboxane A2. Thus, it is likely that the main ROS involved in vasoconstriction in the chorionic plate could be H2O2 and/or O2-. Similar effects have been described in human chorionic vein and isolated perfused cotyledon. In addition, cardiovascular active hormones, such as the insulin, abolished the H2O2-induced contraction (Gonzlez et al., 2011; Rojas et al., 2011). The mechanisms involved in placental oxidative stress involve activity of the catalytic subunits of nicotinamide adenine dinucleotide phosphateoxidase (NADPH oxidase) NOX2 and/or NOX4; both of these expressed in human endothelial cells (Drummond et al., 2011). Recently it was demonstrated that NOX4 could synthesize H2O2 (Takac et al., 2011), thus supporting the possibility that the H2O2 is a relevant ROS in oxidative stress mediated by NOX4. However, the main ROS or RNS involved in the alterations in fetoplacental blood flow seen in PE is still unclear. In the other hand, L-arginine, precursor of NO, is implicated in the fetoplacental regulation of vascular tone. In fetal plasma from PE pregnancies there is a
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decrease in L-arginine concentration correlated with an increase of the expression of human cationic amino acid transporters 1 (hCAT-1) and arginase II (ARGII) in the placental villi from pregnant women with PE (Noris et al., 2004). Arginases are enzymes constitutively expressed in the vascular endothelium with ARGII as the predominant isoform. ARGII catalyses the hydrolysis of L-arginine into urea and ornithine, and evidences show that the catalytic activity of arginases in endothelial cells limits the NO synthesis and the NO-dependent vasodilatation (Morris, 2009). In HUVEC exposed to hypoxia there is an upregulation of ARGII associated with reduced eNOS activity by a mechanism most likely involving colocalization of ARGII with eNOS. This potential colocalization results in reduced substrate availability for eNOS inducing oxidative stress derived from eNOS uncoupling (Prieto et al., 2011). Hypoxia is a physiological condition in the placenta from normal pregnancies. In fact, foetuses whose mothers have normal placental perfusion are exposed to intervillous O2 levels of 8-11%. Abnormal placentation in PE results in lower O2 delivery to the fetus, but the hypoxia per se is not enough to explain the alterations in the newborn associated with PE (Davis et al., 2012a). Thus, a link between hypoxia and oxidative stress in early stages of PE is proposed. In placental explants, hypoxia increases the synthesis of O2-, an effect blocked by activation of hemeoxygenase 1 (HO-1) (George et al., 2012), an enzyme involved in antioxidant responses, angiogenesis, vasculogenesis and early placentation (Grochot-Przeczek et al., 2012; Marcantoni et al., 2012). In addition, activation of HO-1 is related with attenuation of O2- levels, NADPH oxidase activity and increase in the arterial pressure in animal models of placental ischemia-induced hypertension (George et al., 2011). Thus, oxidative stress and hypoxia are in a close interaction and involve the regulation of signalling pathways related with synthesis of ROS, decrease activity of antioxidant enzymes, reduced vasodilation and lower supply of O2 to the fetus. Unfortunately, it is still unclear whether the oxidative stress is an early state or a consequence of the alterations in trophoblast invasion and placentation, but a correlation between the hypoxia caused by poor placentation and increased levels of O2and/or ONOO- in placenta or umbilical cells seems clear.
9. Proteomics in preeclampsia
Preeclampsia-associated complications are responsible for the increased obstetric and paediatric risk (Firoz et al., 2011), and have a permanent impact in the health in adult life (Tuovinen et al., 2012). When the PE is
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diagnosed (usually after 20 weeks) the syndrome is probably established and potential adverse perinatal outcome is likely (Grunewald, 2011). Thus, proteomics is a valuable tool for the identification of proteins or peptides that are informative about the risk in presymptomatic pregnant women who later develop pregnancy complications. One of the most common methods is two-dimensional polyacrylamide gel electrophoresis (2D-PAGE) and Mass Spectrometry (MS). These methods are conceptually simple, i.e., proteins are separated by isoelectric point (pI) in a first dimension followed by separation by its molecular weight (Choolani et al., 2009). Several studies show different expression protein patterns in trophoblasts and plasma proteins at the blood-tissue interface from placenta in PE, which are participating in multiple processes including the hormone biosynthesis and metabolism (Cox et al., 2011). Studies performed in trophoblasts from placentas obtained from PE revealed that expression of 11 proteins was reduced in PE, including actin, glutathione S-transferase, peroxiredoxin 6, aldose reductase, heat shock protein 60, two molecular forms of heat shock protein 70, -tubulin, subunit proteasome, ezrin, protein disulphide isomerase and phosphoglycerate mutase 1; however, only -2-HSglycoprotein (fetuin) was found increased in samples from PE (Johnstone et al., 2011). Altogether these findings are of interest since many of the proteins have been associated with a reduced cytotrophoblast response to oxidative stress. Studies using placental tissue from full-term pregnancies show that apolipoprotein A1 was accumulated in the placenta from PE (Centlow et al., 2010; Zhang et al., 2011a). Other studies using two-dimensional electrophoresis (2-DE) and matrix-assisted laser desorption ionization time of flight mass spectrometry (MALDI-TOF-MS) found overexpression of Hsp27 and Hsp90 in the placenta from PE (Gharesi-Fard et al., 2010; Shin et al., 2011). These results suggest that oxidative stress exists in the placenta from PE perhaps leading to a reduced cytotrophoblast defence and response to oxidative stress. Also there is down-regulation of proteins with antioxidant activities (peroxiredoxin 2 and peroxiredoxin 3), supporting the latter feasibility in PE. In addition, altered expression of the stressresponsive proteins Hsc70, Hsp gp96 and protein disulphide isomerase, might play a role in the pathogenesis of PE. Other studies performed in homogenized chorionic villus explants by MS/MS spectra show that the protein calcyclin (involved in promoting the growth and proliferation of diverse cancer types) (Zhang et al., 2011b) is overexpressed in PE (de Groot et al., 2007; Gzel et al., 2011). These data complement other assays performed in HUVEC exposed to plasma from women with PE where a reduced expression of structural proteins such as
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cytokeratin, actin--1 and moesin, and the calcium-binding protein calumenin (Sankaralingam et al., 2010b). Similar results were found in HUVEC incubated with peroxynitrite scavenger FeTPPS ((5,10,15,20tetrakis(4-sulfonatophenyl)prophyrinato iron (III) chloride) and subjected to 2D gel electrophoresis and mass spectrometry (Sankaralingam et al., 2010a). These results suggest that the prooxidant and nitrating agent ONOO- might damage a wide range of molecules in the cells including DNA and proteins that are altered in PE. Despite the great advances in proteomic techniques there are still several problems such as low reproducibility and detection. In this context, the gelfree strategies represent a breakthrough in mass spectrometry. In this technique there is a fractionation of the peptide, which is produced by liquid chromatographic (LC), as long as proteins remain in solution. Data obtained with this technique identifies 499 proteins in term placental. A fraction of these proteins (45 proteins) were differentially expressed including IL-8 (Blankley et al., 2011). Additionally, serum from patients with diagnoses of PE as well as in asymptomatic women that later on were diagnosed with PE has also been analysed. The results show that antiangiogenic proteins are higher in women with clinical PE compared with the proteomic profile obtained in women with preclinical PE (Rasanen et al., 2010). In addition, using one peptide ligand library combining with 1D gel-LC-MS/MS analysis it was shown that the chorionic human chorionic somatomammotropin hormone (CSH1) was overexpressed in serum from patients with PE (Liu et al., 2011). These findings suggest that the metabolism of the mother is altered in the sense of ensuring delivery of D-glucose to the fetus to comply with energy demand and delivery of proteins for fetal growth. Other experiments show significant reduction in the H-ficolin (1.3 fold) and L-ficolin (3.2 fold) expression in plasma from women with PE (Wang et al., 2007). Ficolins are pattern-recognition lectins involved in the lectin-complement pathway, and play an important role in innate immunity, which might be responsible for the systemic inflammatory response seen in PE. In addition, analysis of urine samples from patients with severe or mild PE and normotensive controls by using surface-enhanced laser desorption ionization time-of-flight mass spectrometry (SELDI-TOF-MS) a different Preeclampsia Proteomic Score of Urine (PPSU) was found compared with subject with normal pregnancies (Lee et al., 2011). In another assay, using isobaric tagging for relative and absolute quantification (iTRAQ) coupled with Two-Dimensional Multidimensional Liquid Chromatography Tandem Mass Spectrometry, a total of 113 proteins were found differentially expressed when compared urine samples from women with PE compared with women coursing with a normal pregnancy (Chen et al., 2011; Zhang et al., 2011a).
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These proteins were associated with several biological processes including blood coagulation, cell adhesion and differentiation, immune response and cytoskeleton development. In the latter study the urinary angiotensinogen (AGT), which is higher in PE by conventional ELISA determination, show the same result when compared with a proteomic approach. Mass spectrometry has exponentially increased in the recent years, and its development responds to the need of finding specific biomarkers that could lead to a better clinical diagnose and management and that will determine the susceptibility of pregnant women to develop PE before that the symptoms appear.
10. Concluding remarks

Preeclampsia is a syndrome with high incidence worldwide that courses with alterations in the fetoplacental vascular function, with clear alterations in the macro and microvascular endothelium of the placenta. Among the several hypotheses it is proposed that abnormal L-arginine/NO signalling pathway is key in the aetiology of the syndrome. It has been proposed that a key role is played by the endogenous nucleoside adenosine, which acts via adenosine receptors, most likely A2AAR, in the endothelium. This phenomenon is a likely a potential defence mechanism for PE-associated altered endothelial function. Along with this specific mechanism, several other metabolic pathways seem involved in the aetiology or at least are making more susceptible the patients to develop this syndrome. Thus, pregestational as well as obesity in pregnancy and dyslipidaemia, along with altered protein expression profiles could be determinant in the onset of PE. In addition to this, insulin and the involvement of the two isoforms of insulin receptors, IR-A and IR-B, and its differential expression in placenta tissue from PE could be determinant in understanding the role of insulin in this syndrome. It is feasible that a differential action of insulin on these isoforms of insulin receptors could be the bases of a future selective therapy to improve endothelial cell function. Adenosine could, in fact, play a role in this phenomenon since adenosine activation of A2AAR seems to be required to allow the biological effects of insulin in human umbilical macro and microvascular endothelium (Guzmn-Gutirrez et al., 2011; Leiva et al., 2011; Pardo et al., 2012).
Acknowledgements
Supported by Fondo Nacional de Desarrollo Cientfico y Tecnolgico (FONDECYT 1110977, 1120928, 11110059, 1100684), Comisin Nacional de Investigacin en Ciencia y Tecnologa (CONICYT PIA Anillos ACT-73,
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AT-24100210), Chile. Instituto de Salud Carlos III-Subdireccin General de Evaluacin y Fomento de la Investigacin, PN de I+D+I 2008-2011 (PS09/01395), Junta de Andaluca, Consejera de Salud (PI-0034), Agencia Espaola de Cooperacin Internacional para el Desarrollo (AECID) (D/031187/10, A1/036123/11), Spain. FP holds a postdoctoral position (CONICYT 3130583 and previously a CONICYT PIA ANillos ACT-73 postdoctoral research associate at CMPL, Pontificia Universidad Catlica de Chile (PUC)). PA, CS, FW and EG-G hold CONICYT-PhD (Chile) fellowships. PA and CS hold a Faculty of Medicine, PUC-PhD fellowship. The authors thank the personnel of the labor ward at the Division of Obstetrics and Gynaecology, PUC.
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Recent Res. Devel. Physiol., 6(2012): 105-158 ISBN: 978-81-308-0489-7

7. Fetoplacental vascular pathophysiology in preeclampsia

Luis Sobrevia et al.

Fetoplacental vasculature in preeclampsia

Luis Sobrevia et al.

Fetoplacental vasculature in preeclampsia

2.1. The fetus in preeclampsia

Luis Sobrevia et al.

2.2. The placenta in preeclampsia

Fetoplacental vasculature in preeclampsia

3. Vascular dysfunction in preeclampsia

3.1. Regulation of placental vascular tone in preeclampsia

Luis Sobrevia et al.

Fetoplacental vasculature in preeclampsia

3.2. Preeclampsia and intrauterine growth restriction

Table 1. Alterations in preeclampsia coursing with or without intrauterine growth restriction.

Luis Sobrevia et al.

Fetoplacental vasculature in preeclampsia

4. Adenosine in the placenta from preeclampsia

Luis Sobrevia et al.

Fetoplacental vasculature in preeclampsia

4.1. Adenosine receptors and preeclampsia

Luis Sobrevia et al.

4.2. Adenosine transporters and preeclampsia

Fetoplacental vasculature in preeclampsia

5. Preeclampsia and obesity in pregnancy

Luis Sobrevia et al.

5.2. Cytokines/interleukins and obesity in pregnancy

Fetoplacental vasculature in preeclampsia

Luis Sobrevia et al.

5.3. Leptin and obesity in pregnancy

Fetoplacental vasculature in preeclampsia

Table 3. Maternal and umbilical cord leptin levels in preeclampsia.

6. Insulin resistance and vascular dysfunction in preeclampsia

Luis Sobrevia et al.

6.1. Impaired insulin signalling

Fetoplacental vasculature in preeclampsia

6.2. Insulin and programming

Luis Sobrevia et al.

Fetoplacental vasculature in preeclampsia

7.1. Endothelial dysfunction and dyslipidaemia in preeclampsia

Luis Sobrevia et al.

7.2. Atherosclerosis and dyslipidaemia in preeclampsia

Fetoplacental vasculature in preeclampsia

7.3. Dyslipidaemia in preeclampsia and fetal programming

Luis Sobrevia et al.

7.4. Preeclampsia, hypercholesterolemia and insulin signalling

8. Free radicals in preeclampsia

Fetoplacental vasculature in preeclampsia

Luis Sobrevia et al.

Fetoplacental vasculature in preeclampsia

Luis Sobrevia et al.

Fetoplacental vasculature in preeclampsia

10. Concluding remarks

Luis Sobrevia et al.

Fetoplacental vasculature in preeclampsia

Luis Sobrevia et al.

Fetoplacental vasculature in preeclampsia