Pregnancy Hypertension: An International Journal of Women’s Cardiovascular Health 1 (2011) 191–196

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Review

Angiogenin and apoptosis in hypertension in pregnancy Vellore J. Karthikeyan, Gregory Y.H. Lip, Deirdre A. Lane, Andrew D. Blann ⇑ University of Birmingham Centre for Cardiovascular Sciences, City Hospital, Birmingham B18 7QH, United Kingdom

a r t i c l e

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Article history: Received 2 June 2011 Accepted 4 July 2011 Available online 19 July 2011 Keywords: Hypertension Gestational hypertension Pre-eclampsia Eclampsia Angiogenesis Apoptosis Angiogenin Vascular endothelial growth factor Serum Fas Serum Fas ligand

a b s t r a c t Hypertension is a common medical condition that complicates pregnancy, and has significant adverse effects on pregnancy outcomes, including maternal and perinatal morbidity and mortality. In seeking the aetiology of pregnancy-related hypertension there has been a shift in focus from the foeto-placental axis to the maternal vasculature, and two possibly related pathophysiological mechanisms have been introduced – angiogenesis and apoptosis. Both processes have been extensively studied as possible pathophysiological mechanisms underlying a variety of diseases, including cardiovascular diseases such as hypertension, myocardial infarction, as well as conditions such as malignancy states, and there is a slowly developing body of knowledge justifying hypothesis of roles in pregnancy. This review presents the data regarding this position and explores the role of angiogenesis and apoptosis in the pathogenesis of hypertension in pregnancy and their effects on pregnancy outcomes. Crown Copyright Ó 2011 International Society for the Study of Hypertension in Pregnancy Published by Elsevier B.V. All rights reserved.

Introduction With a frequency of 2–3%, hypertension is the most common medical problem encountered during pregnancy. Hypertensive disorders during pregnancy are the second leading cause, after embolism, of maternal mortality in the United States, accounting for almost 15% of such deaths. Hypertensive disorders occur in 6–8% of pregnancies and contribute significantly to stillbirths and neonatal morbidity and mortality [1,2]. The causes of most cases of hypertension during pregnancy, particularly pre-eclampsia, remain unknown, although one of the first hypotheses focused on abnormal vascular reactivity and the overproduction of vasoactive substances such as angiotensin II by the foetal/placental system [3,4]. Subsequent hypotheses predicted a role for factors such as endothelial cell activation, nitric oxide and misaligned trophoblast ⇑ Corresponding author. Tel.: +44 121 507 5080; fax: +44 121 507 5907. E-mail address: [email protected] (A.D. Blann).

invasion [5–8]. More recently, it has been suggested that abnormalities in angiogenic growth factors (e.g. vascular endothelial growth factor [VEGF], angiopoietin, and more recently, angiogenin) and apoptosis may be important [9–13]. This review article aims to provide an overview of current literature and concepts relating abnormalities in angiogenesis and apoptosis and the hypertensive disorders in pregnancy. To achieve this aim we performed an on-line search of publication databases Cochrane Reviews, PubMed, MEDLINE and EMBASE, using the key words angiogenesis, apoptosis, hypertension and pregnancy. In order to identify any unpublished studies, abstracts from national (British Cardiac Society, Medical Research Society) and international (American Heart Association, American College of Cardiology, European Society of Cardiology), cardiology conferences in 2007 through 2010 were inspected. The reference lists of all papers yielded by the electronic database were scrutinised to identify any other potentially relevant articles.

2210-7789/$ - see front matter Crown Copyright Ó 2011 International Society for the Study of Hypertension in Pregnancy Published by Elsevier B.V. All rights reserved. doi:10.1016/j.preghy.2011.07.002

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Hypertension in pregnancy Hypertensive disorders may be classified into four categories: chronic hypertension, pre-eclampsia-eclampsia, pre-eclampsia superimposed upon chronic hypertension, and gestational hypertension. Chronic hypertension is defined as hypertension (blood pressure P 140 mm Hg systolic and/or P90 mm Hg diastolic) that is present and observable before pregnancy or diagnosed before the 20th week of gestation. Hypertension diagnosed for the first time during pregnancy and that does not resolve postpartum is also classified as chronic hypertension. Preeclampsia-eclampsia is a pregnancy-specific syndrome that usually occurs after 20 weeks’ gestation, or earlier in trophoblastic diseases (hydatidiform mole or hydrops). The increased blood pressure is accompanied by proteinuria in this syndrome. This can develop into full-blown pre-eclampsia, a syndrome characterised by hypertension, proteinuria and symptoms of headache, visual changes, epigastric or right upper quadrant pain and dysponea. It may be mild or severe, depending on the degree of hypertension, proteinuria and other organ system involvement, and requires treatment by specialists [1,2,14].

Angiogenesis in pregnancy Normal intrauterine foetal development is dependent on adequate nutrient and substrate supply. Vasodilatation and development of new vessels both enable the adaptation of the uterine vasculature to the rising needs of the foetus. Angiogenesis is the process of neovascularisation from pre-existing blood vessels in response to hypoxia or substrate demands of tissues, and as such is a complex biological process comprising many steps that are precisely regulated by several molecules [15,16]. An initial step is the vasodilatation of the pre-existing vessel and formation of vesiculo-vacuolar organelles in the endothelial cells. The most important effector for this step is VEGF [17]. Subsequently, vessel destabilization and matrix degradation occur, as perivascular stroma needs to be remodelled. Angiopoietin 2 and proteases (such as chymases and matrix metallo-proteinases) are involved in this step. Endothelial cell proliferation and migration along a gradient of chemotactic agents then proceeds through the disintegrated basement membrane into the remodelled and softened perivascular space [18]. Specific mitogens of endothelial cells in this step are VEGF, angiopoietins, and fibroblast growth factor, epidermal growth factor, CXCchemokines and insulin-like growth factor type 1, which induce the proliferation of several types of cells. This leads to lumen formation and vessel stabilization, by the migrated endothelial cells first forming a monolayer and then tube-like structures with surrounding mesenchymal cells and vascular smooth muscle cells. Different forms of VEGF and integrins have been implicated in this step [19]. In the pregnant uterus, the endometrium, decidua and placenta are sources rich of angiogenic growth factors. Angiogenic process is initiated by growth factors such as basic fibroblast growth factor (bFGF), VEGF, or placental growth factor (PlGF) [20,21]. Whilst the role of these growth factors is

established, others, such as angiogenin, may also be important. Angiogenin Angiogenin is a member of the ribonuclease (RNase) super family. The RNases are enzymes of innate substrate specificity, but divergent functional capacities, whose distinct structure confers on angiogenin an endothelial binding motif, which it combines with its endonuclease enzyme activity and produces a potent stimulus for blood-vessel formation [22]. Physiologically, angiogenin is also induced during inflammation, exhibiting wound healing properties as well as microbiocidal activity and conferring host immunity. Markedly high levels of angiogenin can be found in the circulation without proliferative impact. Angiogenin (or RNase 5) is a 14 kDa soluble protein, first isolated from the culture medium conditioned by colon carcinoma (HT-29] cells [23]. The 123 amino acid chain and corresponding nucleotide sequences of angiogenin show 33% sequence identity and 65% homology with pancreatic RNase 1 (RNase A) [24]. The tertiary structure of angiogenin still contains many of the tertiary facets of peptide folding as seen in RNase 1, with the conservation of all key alpha helices and beta sheets [25]. Eight members have been identified in the RNase super family, and whilst each has distinct biological effects, all share a common enzymic ribonucleolytic activity on RNA [26]. In the case of angiogenin, RNase activity is directed towards 28S and 18S rRNA with the major products being 100–500 nucleotides in length [27]. Evolutionary analysis of the angiogenin lineage from non-mammalian species suggests that angiogenin and RNase 4 (closest family member to angiogenin) represent the most ancient forms of the RNase super family [28]. Recently, it has been established that angiogenin acts as an endogenous microbiocidal agent against systemic bacterial and fungal pathogens [29], extending a role for innate immunity for the rest of the RNase super family. Angiogenin is present in plasma, in normal subjects, in a concentration of about 250–360 lg/L [28]. During human development, angiogenin has been detected in organs such as heart (in a foetus at 19 weeks), spleen (foetus at 19 and 20 weeks), lung (foetus at 19 week and adults), liver (foetus at 20 week and adult), colon, prostate, breast, brain, retina, melanocyte and foreskin (only in adults) [24,30–32]. However, angiogenesis does not take place continuously in all tissues, at all stages, as angiogeninmediated angiogenesis requires a catalytic substrate and a cell surface receptor. Angiogenin expression is stimulated by the RNA that is likely to be released during apoptotic and necrotic cell damage in wound healing. One possible source of plasma nucleic acids that may induce RNAases is likely to relate to the phagocytotic activity of macrophages on dead cells [33], or perhaps release by apoptotic cells. Angiogenin in pregnancy The human placenta is one of the best in vivo models of physiological angiogenesis. Blastocyst-derived trophoblast

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cells invade the endometrium leading to remodelling of the spiral arterioles into maximally dilated low resistance vascular channels, which enables a high flow volume into the developing utero-placental bed [34]. Hypoxia is a stimulus to increase the expression of mRNA and secretion of angiogenin in trophoblasts, at least in a human placenta experimental model [34]. Angiogenin levels increase from 150 to 250 ng/mL between weeks 10 and 40 in uncomplicated pregnancies [35], and during the first four postnatal days, there is a rapid increase in maternal serum angiogenin levels following healthy full-term pregnancies [36]. Angiogenin probably has an important role in normal vascular development, as angiogenin levels are significantly decreased in patients with highly pathologic uterine Doppler flow, compared with healthy pregnancies [34]. Of note, pre-eclamptic patients who delivered low birth weight infants had higher levels of angiogenin than those who delivered infants with normal birth weight [35]. Pavlov et al. [37] studied the expression of angiogenin in situ and in vitro, using the human term placenta as a model of physiological angiogenesis. Angiogenin was immunodetected by light and transmission electron microscopy, and its cellular distribution was established by double immunolabelling with a panel of endothelial cell markers. Angiogenin immunoreactivity was widely detected in villous and extravillous trophoblasts, the trophoblast basement membrane, the endothelial basal lamina, foetal blood vessels, foetal and maternal red blood cells, and amnionic cells. Villous cytotrophoblasts, isolated and differentiated in vitro into a functional syncytiotrophoblast, expressed and secreted angiogenin. Their data suggested that, in human placenta, angiogenin has a role not only in angiogenesis but also in vascular and tissue homeostases, maternal immune tolerance of the foetus, and host defences. Angiogenin has been studied alongside VEGF by three groups. Shaarawy et al. [38] recruited 71 pregnant women with pre-eclampsia and 20 normotensive pregnant

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controls, finding maternal serum VEGF and angiogenin levels were significantly increased in cases of mild and severe pre-eclampsia compared to controls. This increase was positively correlated with elevated systolic and diastolic blood pressure, as well as abnormal Doppler velocimetry, and low birth weight. Their findings suggested a possibility of vascular reactivity and endothelial disturbance in preeclampsia, with measurement of these angiogenic factors in maternal serum as biomarkers for the assessment of the severity of the disease and of foetal outcomes. Lassus et al. [39] measured VEGF and angiogenin in umbilical cord blood from 14 foetuses with erythroblastosis or alloimmune thrombocytopenia and at birth from 28 preterm foetuses, from 42 healthy term foetuses, and from 24 term foetuses born to mothers with insulin-treated diabetes, noting a significant correlation between VEGF and angiogenin levels. Gestational age correlated with both VEGF and with angiogenin, and VEGF levels were found to be lower in foetuses born to diabetic mothers than in the healthy term foetuses, although this difference was absent for angiogenin. Thus they found a developmental increase in concentrations of VEGF and angiogenin in umbilical cord plasma during the last trimester of gestation. The lower umbilical cord VEGF levels in term foetuses born to mothers with diabetes compared with those of healthy mothers may be secondary to abnormal foetal vascular development in diabetic pregnancies. Karthikeyan et al. [40] reported lower levels of angiogenin and VEGF in 38 normal and 38 hypertensive pregnancies compared to 50 non-pregnancy. In the hypertensive pregnancies, angiogenin was not significantly different at 15 weeks of pregnancy compared to 30 weeks, implying low levels are present early in pregnancy and are fixed. However, although these studies are informative, it is clearly far too early to determine whether or not angiogenin has more to offer than does VEGF, in either clinical or pathophysiological matters. Table 1 summaries the major studies in this field.

Table 1 Angiogenesis and pregnancy. Study

Patients (n)

Markers studied

Shaarawy et al. [38]

Pre-eclampsia (71) Normotensive pregnant women (20)

VEGF, angiogenin

Nadar et al. [75]

Pregnancy induced hypertension (PIH) (69, pre-eclampsia, n = 35) Normotensive pregnant women (64) Non-pregnant controls (30) Pre-eclampsia (19) Normotensive pregnant women (19)

VEGF, angiopoietins (Ang-1, Ang-2), and their soluble receptors Flt-1 (sFlt-1) and Tie 2 (sTie-2)

Kupferminc et al. [76]

Baker et al. [77]

Pre-eclampsia (27) Non-proteinuric PIH (15) Normotensive pregnant women (36)

VEGF

VEGF

Findings  Significantly raised VEGF and angiogenin levels in mild and severe pre-eclampsia.  Positive correlation between their raised levels and poor bio-physical score, abnormal umbilical and uterine artery Doppler velocimetry and low birth weight.  Significant differences in plasma VEGF, Ang-1, Ang2, sFlt-1 and Tie-2 between the study groups.  Ang-1 highest in the pre-eclampsia group (p < 0.001).  Ang-2 highest in the normotensive pregnant group (p = 0.018).  Plasma Tie-2 highest in the PIH group.  VEGF levels significantly different between the pre-eclampsia group and the PIH group (p < 0.05).  Significantly raised VEGF levels in pre-eclampsia (p < 0.001);  Positive correlation between VEGF and systolic and diastolic blood pressures in the preeclamptic group (r = 0.56; p = 0.01 and r = 0.48; p = 0.037, respectively).  VEGF levels below the lower limit of detection.  The proportion of detectable levels higher in the pre-eclampsia group (7/27) than in the normotensive group (1/36, P < 0.05).

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Apoptosis Apoptosis, the process of programmed cell death, has been implicated in the pathophysiology of pre-eclampsia [41]. A working hypothesis states that inappropriate apoptosis of trophoblast cells (be they cytotrophoblast and/or synctotrophoblast) leads more or less directly to poor vascularity and thus inadequate placentation, and ultimately pre-eclampsia and foetal problems such as intra-uterine growth retardation [42,43,12]. The Fas/Fas ligand (Fas/FasL) system is one of the main apoptotic pathways and is expressed in immune as well as non-immune cells, including trophoblasts [44]. Its expression and function responds to changes in the microenvironment, and play a pivotal role in controlling cell proliferation and tissue remodelling. CD95 (Fas) is a type I membrane protein of 45 kDa that belongs to the TNF receptor family of proteins. FasL, a type II membrane protein of 37 kDa, belongs to the TNF and CD40 ligand family of proteins. Fas is widely expressed in many tissue types. In T and B cells, it is present constitutively in low levels on the surface of resting cells and its expression is enhanced following lymphocyte activation. In contrast to Fas, the expression of FasL is reported to be more restricted and often requires cell activation. The binding of the Fas receptor by FasL results in downstream activation of a cascade of intracellular proteolytic enzymes, such as caspases, ending in apoptosis [45,46]. The Fas/FasL system and pregnancy There is a considerable literature base demonstrating a role for Fas/FasL in pregnancy, many of which highlight regulated physiological apoptosis as part of an immunological response to the foetus [47–50]. For example, some suggest a role for complex reversible molecular mechanisms including intradecidual T cell tolerance that occur during and soon after implantation of the conceptus [45,51]. There is also evidence for endothelial cell and smooth muscle cell apoptosis driven by Fas/FasL [52,53]. Abberations in the Fas/FasL system have also been implicated in disorders of pregnancy [54–57], including pre-eclampsia. The importance of the trophoblast in the pathophysiology of pre-eclampsia is clear, with reports of increased apoptosis of the extravillous trophoblast in the

placental bed. The increased apoptosis may be secondary to an increase in trophoblast sensitivity to Fas-mediated apoptosis or an increase in material presented to a normally functioning cytotrophoblast/syncytiotrophoblast system [42,58,12,59,60]. The higher proliferation rate introduces more material into the syncytiotrophoblast via fusion and the multinucleated layer increases its apoptotic release of material as a counterbalance. Hence the increase in apoptosis is perhaps a sign of higher turnover of villous trophoblast secondary to an adaptive process. An increase in Fas expression coupled with decreased FasL expression in the villous trophoblast has been demonstrated [61]. Serum from preclamptic women has been shown to reduce trophoblast viability, and that effect seemed to be related to changes in trophoblast sensitivity to Fas-mediated apoptosis [62]. Furthermore, deportation of villous trophoblast debris (perhaps from apoptoic cells] directly into the maternal circulation is implicated in the genesis of an exaggerated intravascular maternal inflammatory response in pre-eclampsia [63]. This may part-explain the link between the aberrant placentation and activated maternal endothelium seen in pre-eclampsia. Whilst the Fas/FasL system operates between cells, soluble forms of both molecules may be found in the plasma [64,65]. Indeed, it has been suggested that soluble Fas protects various trophoblast cells from apoptosis [66]. Whilst low soluble Fas is present in normal pregnancy compared to non-pregnancy, an increase in soluble Fas has been noted in pre-eclampsia [67–69] although Kuntz et al. have been unable to confirm this increase [70]. Karthikeynan et al. [71] found no differences in soluble Fas between 50 non-pregnant women, 20 normal pregnancies and 20 hypertensive pregnancies (free of pre-eclampsia) at early (week 15) or late (week 30) stages of the gestation. Interestingly, Laskowska et al. found soluble Fas to be higher in umbilical vein blood of neonates born to pre-eclamptic mothers compared to umbilical vein blood from neonates born to normotensive mothers [72]. This indicates abnormalities in the soluble Fas system on both sides of foeto-maternal interface. However, changes in soluble Fas are not specific for pre-eclampsia and are present in other pathology such as intra-uterine growth retardation [73–75]. Parallel data on soluble Fas ligand are weak. Laskowska et al. [69] reported no change in soluble Fas ligand in 11

Table 2 Apoptosis and pregnancy. Study

Patients (n)

Markers studied

Laskowska et al. [69]

Pre-eclampsia (11) Hypertensive pregnant women (12) Pre-eclampsia (20) Normotensive pregnant women (18)

Maternal and umbilical serum soluble Fas and Fas ligand

Kuntz et al. [70]

Hsu et al. [68]

Pre-eclampsia (34) Normotensive pregnant women (34)

Paired maternal and umbilical cord blood serum soluble Fas and Fas ligand

Serum soluble Fas levels

Findings  Increased maternal and umbilical vein serum sFas and increased umbilical vein serum sFasL levels in the study group in comparison with the control group (p < 0.001).  Soluble FasL levels higher in paired maternal and umbilical cord blood (CB) sera of hypertensive gestations (p < 0.01).  Soluble Fas levels similar between the groups.  Surface expression of FasL lower on maternal (p < 0.01) and CB (p < 0.05) neutrophils from affected gestations, whereas surface Fas expression lower on maternal (p < 0.02), but not CB, neutrophils and lymphocytes.  Higher serum soluble Fas levels in preeclamptic women (p < 0.001).

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cases of pre-eclampsia compared to 12 healthy normotensive pregnancies, whilst Kuntz et al. [70] found raised levels in 20 pre-eclamptic hypertensive pregnancies compared to 18 controls. However, Karthikeynan et al. [71] reported lower soluble Fas ligand in hypertensive pregnancies compared to normotensive pregnancies and non-pregnancy. They also found a far higher soluble Fas to soluble Fas ligand ratio in the hypertensive pregnancies. The purpose of measuring the molecules in different disease groups of course hopes to identify a putative disease marker that would have predictive value. The experiments outlined above provide limited opportunity to do so, and far larger studies are required for the degree of sensitivity and specificity concerned. Nevertheless, Harris et al. have speculated that apoptosis triggered by the release of soluble Fas ligand may be an important pathophysiological process [53]. Table 2 summarises major studies.

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[13]

[14] [15]

[16]

[17]

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