university of groningen hydrogen sulfide in preeclampsia ... · complicating approximately 2-5% of...
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University of Groningen
Hydrogen Sulfide in PreeclampsiaHolwerda, Kim
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Ch a pte r 1General Introduction
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10 | Chapter One
Preeclampsia (PE) is a severe pregnancy-induced syndrome that is characterized by the
new onset of hypertension and proteinuria in the second half of gestation. Symptoms
of PE and eclampsia (the onset of convulsions in PE) were already perceived in ancient
times, and the association between the pregnancy-related disorder and a “heavy”, strong
and swollen pulse’ was made in the 6th century.1 However, it was not until 1896, when
sphygmomanometry was introduced, that blood pressure measurements were clinically
used to diagnose PE.2 In the 19th century, proteinuria in PE patients was first noted by
Lever et al.3 Despite the great development in the area of PE, the etiology of PE is still
partly unclear. Perhaps more importantly, no adequate therapies for PE or methods
to predict PE have yet been developed. Consequently, PE is still a leading cause of
maternal and fetal mortality and morbidity worldwide. Since the last decades, the role of
gasotransmitters such as nitric oxide (NO) and carbon monoxide (CO) in the initiation and
progression of PE have been investigated. The gases are thought to be involved in the
pathophysiology of PE, and exogenous administration NO, CO, or related compounds
have beneficial effects in (animal models for) PE. The most recently discovered and third
gasotransmitter hydrogen sulfide (H2S) has never been investigated in PE. However, its
vasodilatory and pro-angiogenic features make H2S an interesting factor to investigate in
PE. This prompted us to explore the involvement of H2S as a novel factor in the (patho)
physiology of pregnancy and PE, and to investigate the possibilities of H2S to become a
therapeutic agent for this severe pregnancy-related disease.
Preec lamps ia
Complicating approximately 2-5% of all pregnancies worldwide, PE is a major obstetric
problem contributing to both maternal and fetal mortality and morbidity.4 It is a multi-
organ disease that clinically manifests after the 20th week of gestation.5,6 The disease
is defined by the new onset of hypertension (systolic blood pressure ≥ 140 mmHg and/
or diastolic blood pressure ≥ 90 mmHg), in combination with proteinuria (≥ 300 mg / 24
hours). PE can be subdivided into an early-onset form, with an onset before 34 weeks of
gestation, and a late-onset form, developing after 34 weeks of gestation.
Both the maternal and perinatal outcomes of PE worsen with an earlier gestational
age at time of onset and with increased severity of the disease. PE can affect several
organs, such as the maternal liver, the kidneys, and the brain. Therefore, maternal
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General Introduction | 11
complications of PE include the HELLP syndrome (hemolysis, elevated liver enzymes, and
low platelets), renal failure, and eclamptic seizures. In the kidney, PE is also associated
with glomerular endotheliosis, which is thought to be a pathognomonic lesion in PE.
Glomerular endotheliosis is mainly characterized by the presence of protein droplets
and by occlusion of capillary lumens by swollen endothelium.8 Fetal complications of PE
include preterm delivery and fetal growth restriction.5,6
The only effective treatment for PE at the moment is termination of pregnancy (delivery
of the placenta), often remote from term. Management options for PE are accurate
maternal and fetal monitoring, and avoiding maternal complications by administering
anti-hypertensive drugs. Obviously, management decisions are highly dependent on
the severity of the disease and the gestational age of presentation.6 The right balance
between the risk for the mother to be subjected to progressive disease and the benefits
for the fetus to further develop in utero, is essential in this decision-making. Ideal
therapeutic strategies that prolong pregnancy until term and prevent further progression
of the maternal disease have not been developed yet.
Pathogenesis of preeclampsia
Although the etiology of PE is still not completely understood, the general hypothesis
that the placenta plays a key role in its pathophysiology is leading.5,6 However, it is now
becoming clear that the extent to which the placenta contributes to the disease is variable.
Inadequate placentation is now thought of much greater significance in the development
of early-onset PE, rather than in the late-onset form. Late-onset PE, on the other hand,
seems to be more associated with a defective pre-gestational maternal endothelium and/
or inflammatory function.9
The development of early-onset PE is thought to progress in two stages, starting
with a preclinical phase, which is associated with abnormal placentation in the early
stages of pregnancy (stage I).5,10 During the process of placentation in normal pregnancy,
fetal cytotrophoblasts invade the maternal myo- and endometrium, and the spiral
arteries. The cytotrophoblasts migrate into the wall of the spiral arteries, resulting in the
loss of endothelial and vascular smooth muscle cells. Consequently, the spiral arteries
become dilated and low-resistant in order to optimize uteroplacental blood flow during
gestation.5,6 During the development of PE, trophoblast invasion and, consequently,
remodeling of the maternal spiral arteries in the maternal myometrium is impaired (stage
I).5,6 The spiral arteries remain narrow and highly resistant, causing insufficient placental
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12 | Chapter One
perfusion (intermittent flow) and subsequent placental oxidative stress.5,10 Subsequently,
the hypoxic placenta releases various bioactive compounds into the circulation of the
mother, such as soluble FMS-like tyrosine kinase 1 (sFlt1), pro-inflammatory cytokines,
and syncytiotrophoblast microparticles.5,6 Together, these factors contribute to the
onset of generalized endothelial cell dysfunction and vascular inflammation, which
are consequently thought to initiate the clinical syndrome of PE, i.e. hypertension and
proteinuria (the clinical stage; stage II).10,11 Early-onset PE is often accompanied by fetal
growth restriction, since the oxygen-deprived placenta is not able to meet the increasing
fetal demands for nutrients and oxygen along with gestation.5
For late-onset PE, maternal factors that predispose to vascular inflammation seem
to be relevant. In these women, pregestational endothelial dysfunction is present, due
to preexisting conditions such as (early stages of) cardiovascular disease, obesity, or
diabetes.9 It is thought that the preexisting vascular inflammation exaggerates the maternal
response to pregnancy and contributes to the clinical signs of PE.9,12 However, another
hypothesis with regard to the development of late-onset PE was recently proposed.13 As
with the early-onset form, inadequate placental perfusion is observed in late-onset PE.
The dysregulation of placental perfusion in late-onset PE, though is not preceded by
impaired placentation, but by restricted villous perfusion that is associated with the size
of the term placenta.13 As in early-onset PE, dysregulation of placental perfusion in late-
onset PE causes placental stress, release of bioactive compounds, and the subsequent
clinical stage (stage II) of PE.
Anti-angiogenic factors belong to the variety of bioactive factors that are released
by the affected placenta during PE.10,11 These factors contribute to the development of
endothelial cell dysfunction, a central feature of PE.14 The most extensively researched
anti-angiogenic factor in PE is sFlt1. The sFlt1 protein is a splice variant of vascular
endothelial growth factor (VEGF) receptor 1, lacking the transmembrane and cytoplasmic
domains.15 Circulating in the maternal blood, sFlt1 acts as a powerful antagonist of VEGF
and placental growth factor (PlGF). Increased levels of circulating sFtl1 lead to functional
VEGF and PlGF deficiency, causing endothelial dysfunction, impaired angiogenesis,
impaired capillary repair, and, consequently, hypertension and proteinuria.16,17 Moreover,
aside from the release of antiangiogenic factors, the diseased placenta sheds pro-
inflammatory debris into the maternal circulation containing factors such as cytokines and
syncytiotrophoblasts microparticles.18-20 These factors activate the maternal endothelium
and consequently contribute to the endothelial dysfunction and vascular inflammation.20
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General Introduction | 13
therapeutic strategies for preeclampsia
Various options have been studied as potential therapies for PE, including anti-oxidants
(such as vitamin E), fish oil, and bed rest.21-23 Unfortunately, none of these studies have been
convincing. Supplementation of calcium and the use of aspirin started early in gestation
have been shown to have small beneficial effects in the prevention of PE in high-risk
populations.24,25 Currently, quite a few studies focus on restoring the angiogenic balance
during PE. Recent studies have shown that recombinant proteins with functions similar to
VEGF have therapeutic effects in animals with experimental PE.26-28 Furthermore, selective
removal of plasma sFlt1 in women with early-onset PE shows beneficial effects.29 Finally,
current studies also focus on the use of gasotransmitters as a therapy for PE. Because of
their regulating function in the vasculature and cytoprotective actions, gasotransmitters
are an interesting target in PE.
Gasotransmitters and preeclampsia
Gasotransmitters, such as nitric oxide (NO) and carbon monoxide (CO), are small,
hydrophilic, gaseous signaling molecules, that diffuse through cell membranes.30 Given
that both NO and CO are involved in regulation of vascular tone and that deficiency of the
two gases is associated with endothelial dysfunction, their role in PE has been extensively
studied.31-33 It has been shown that the bioavailability of NO and CO is impaired in women
with PE.32,34,35 Moreover, besides their vasoregulating functions, it is believed that NO
and CO might also be involved in influencing the angiogenic balance in PE.36-38 Finally,
increased availability of the cytoprotective heme oxygenase-1 (a CO producing enzyme)
in PE patients was linked to the increased oxidative and inflammatory stress that is present
in these women.39 Supplementation with L-arginine, the precursor of NO, might have a
role in the treatment and/or prevention of PE.40 Clinical trials using therapeutic agents
that target as well the anti-angiogenic environment as NO deprivation, such as statins
and relaxin, are now performed.41-43 Interestingly, statins are also able to increase CO
availability.44 Besides NO and CO, a third gasotransmitter was discovered more recently;
hydrogen sulfide (H2S).
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14 | Chapter One
Hydrogen su l f ide
For a long time, H2S has been known as a highly toxic gas with the distinctive smell
of rotten eggs. However, during the last few decades, the gas was discovered to be
endogenously produced by mammalian cells.30 In humans and other mammals, the
enzymatic H2S production is part of the transsulfuration pathway (figure 1).30 The two main
enzymes in this process are cystathionine-β-synthase (CBS) and cystathionine-γ-lyase
(CSE), both using pyridoxal 5’-phosphate (vitamin B6) as a cofactor.45 CBS performs the
first and rate-limiting step in the transsulfuration pathway by converting homocysteine into
cystathionine. This is followed by cleavage of cystathionine by CSE yielding L-cysteine.
Both CBS and CSE desulferate L-cysteine into H2S (figure 1).45 H2S is also produced
by 3-mercaptopyruvate sulfurtransferase (3-MST) from L-cysteine and D-cysteine, via
cysteine aminotransferase (CAT) and D-amino acid oxidase (DAO), respectively (figure
1).46 Oxidation of H2S yields its metabolites thiosulfate, sulfite, and sulfate, which are
excreted in urine (figure 1).47
Figure 1 - schematic representation of the H2s production pathway
CBS, cystathionine-β-synthase; CSE, cystathionine-γ-lyase; CAT, cysteineaminotransferase; 3-MST,
3-mercaptopyruvate sulfurtransferase; and DAO, D-amino acid oxidase.
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General Introduction | 15
Biological functions of hydrogen sulfide
H2S has several biological functions, such as scavenging reactive oxygen species,
affecting the immune system by e.g. modulating cytokine production and leukocyte
adhesion, and influencing protein activity through sulfhydration.48 However, the first and
most studied function of H2S is regulation of vascular tone. Genetic deficiency of CSE
causes hypertension, as shown by CSE knockout mice, which suffer from age-dependent
hypertension and loss of endothelium-dependent vasorelaxation.49 Mice heterozygous
for CBS also develop increased blood pressure.50 Interestingly, individuals with a genetic
deficiency of CBS exhibit hyperhomocysteinemia, which is associated with vascular
disease and endothelial dysfunction.51,52
Within the vessel wall, H2S is produced by both endothelial cells and vascular smooth
muscle cells and the gas is able to induce vasorelaxation via direct opening of potassium-
ATP (KATP) channels and calcium-dependent potassium channels.43,53,54 It has recently been
shown that opening of the KATP channel by H2S may be initiated by sulfhydration of cysteine
residues in this channel.55 Furthermore, it has been described that the vasodilatory effects
of H2S are partially dependent on nitric oxide (NO),56 and that H2S is able to prevent
hypertension in rat by affecting the renin-angiotensin aldosterone system (RAAS) through
direct inhibition of renin plasma activity.57
H2S is also an efficacious pro-angiogenic agent. The process of angiogenesis is
characterized by the sprouting of new blood vessels. An important mediator in angiogenesis
is VEGF, which exerts its effects through VEGF receptor 2 (VEGFR2). The pro-angiogenic
properties of H2S were first shown by Cai et al. in vitro and confirmed by several other
groups in vivo.58-60 VEGF expression and activation of its receptor are increased upon H2S
treatment.60-62 Interestingly, H2S is also able to directly activate VEGFR2 by breaking a
disulfide bond in a domain of this receptor.63 As with vasorelaxation, the pro-angiogenic
actions of H2S seem to be partially dependent on NO.56,64
Hydrogen sulfide as a therapeutic compound
Decreased production of H2S or its producing enzymes is substantially linked to
the pathology of cardiovascular disease.65 Therefore, compounds able to increase
availability and/or functionality of H2S have been shown to have therapeutic potential
in these diseases. Such compounds can be divided into several groups. In the vast
majority of studies, commercially available sulfide-sodium salts such as NaHS and Na2S
are used. NaHS and Na2S have shown to have pro-angiogenic, antihypertensive and
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16 | Chapter One
antiinflammatory effects.57,60,66 However, a major problem of sulfide-sodium salts is the
rapid loss of sulfide from the solution, making it difficult to achieve controllable levels
of H2S in vivo and in vitro. For this reason, H2S donors with slow-releasing properties are
under development. For example, it was shown that the slow H2S releaser GYY4137 is
able to normalize blood pressure in spontaneously hypertensive rats.67 Another alternative
is the administration of natural occurring analogues of cysteine, the precursor of H2S.
S-propargyl cysteine for example is able to induce angiogenesis in both in vitro and
in vivo settings.68 Moreover, it was observed that the cysteine analogue diallyl trisulfide
(derived from garlic), has protective cardiovascular effects by up regulation of VEGF and
NO bioavailability in mice.62 Finally, the H2S metabolite sodium thiosulfate can also act as
an H2S donor. Through the action of thiosulfate reductase, thiosulfate can be converted
into H2S. It was recently shown that hypertension, proteinuria, and renal damage induced
by angiotensin II infusion was attenuated by sodium thiosulfate.69
Hydrogen sulfide in pregnancy and preeclampsia
The placental production of H2S by CSE and CBS from L-cysteine was first described
in 2009. The endogenous H2S production by the placenta increases under low oxygen
conditions.70 The catalytic activity of CBS was further analyzed by Mislanova et al., showing
that homocysteine increased the accumulation of L-cysteine and CBS in human placental
explants.71 Functionally, it was shown in vitro that H2S mediates vasodilatation within the
human placenta via KATP channels and by interaction with nitric oxide.72 The presence of
CBS was also detected in first trimester human placentae.73
Alterations in the transsulfuration pathway have been associated with PE. For
example, homocysteine, cystathionine, and cysteine are increased in the plasma of
women with PE.74-76 Furthermore, hyperhomocysteinemia has been related to a decreased
fetal weight in the offspring of both healthy pregnant women and PE patients.74,77,78
Interestingly, pregnant CBS-deficient mice, both homozygotes and heterozygotes, exhibit
hyperhomocysteinemia which is associated with blunted endothelial-dependent vessel
relaxation.79 Finally, CBS-deficient mice show impaired decidualization.80
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General Introduction | 17
Scope o f the thes i s
Clinically, PE is recognized by proteinuria and hypertension. Pathological processes, such
as endothelial dysfunction, impaired angiogenesis, and an exaggerated immune response,
are characteristic for PE. As H2S is known for its, immunomodulating, cytoprotective,
vasorelaxative, and pro-angiogenic effects, we hypothesize that decreased H2S is
involved in the pathophysiology of PE and that H2S could have therapeutic potential in
PE. Until now, the expression of the H2S-producing enzymes in pregnancy and PE has
never been investigated. Therefore, the main objective of this thesis is to address these
issues by investigating alterations in the H2S pathway in association with PE and by testing
its therapeutic potential in vivo.
Part I: Human studies – Hydrogen sulfide in the pathophysiology of Pe
In the last decade(s), the role of NO and CO in both pregnancy and PE has been
investigated extensively. Less is known about the involvement of H2S in pregnancy and in
the pathophysiology of PE. As H2S, NO, and CO share several features and functions, a
similar involvement of H2S in pregnancy and PE is conceivable. The aim of Chapter 2 was
to give an outline of the role of the three gasotransmitters in the physiology of pregnancy.
Furthermore, this chapter describes the aberrant production of NO, CO, and H2S in PE.
Specific emphasis is put on the therapeutic potential of the three gasotransmitters in PE
by overviewing experimental in vivo and in vitro studies.
Chapter 3 aims to evaluate the cellular localization of two H2S-producing enzymes,
CBS and CSE, in the human placenta. Moreover, the placental expression of both mRNA
and protein of these two enzymes is investigated during healthy pregnancy and PE.
Expression of CBS and CSE in placentae from both early-onset and late-onset PE patients
is evaluated.
Chapter 4 focuses on the single nucleotide polymorphisms (SNPs) in the CBS gene in
association with early- and late-onset PE. In a cohort of 75 healthy pregnant women, 45
patients with early-onset PE and 52 women with the late-onset form, six tagging SNPs in
the locus of the CBS gene are assessed. Furthermore, functional effects of the tag-SNPs
on plasma and urinary metabolites of the transsulfuration pathway are evaluated in this
chapter.
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18 | Chapter One
Part II: animal studies – Hydrogen sulfide as a therapeutic agent in animal models with
high sFltt
As H2S has pro-angiogenic potential, its therapeutic properties were evaluated in an
animal model in which an anti-angiogenic state was induced by sFlt1 overexpression.
This animal model was first described by Maynard, et al., who showed that injection of an
adenovirus overexpressing the anti-angiogenic protein sFlt1 in pregnant rats induced a
PE-like phenotype.17 As in the human situation, high levels of circulating sFlt1 antagonize
the free circulating levels of the pro-angiogenic protein VEGF. Systemic deprivation of
VEGF contributes to the onset hypertension, proteinuria, and glomerular endotheliosis
in these rats.17 The induction of the phenotype by the sFlt1 adenovirus is not exclusive
to pregnant animals. Therefore, the aim of Chapter 5 was to examine the effect of the
H2S donor NaHS on hypertension, proteinuria and glomerular endotheliosis in a non-
pregnant rat model with sFlt1 overexpression. By performing both in vivo and in vitro
experiments, the mechanism by which NaHS (partly) influences the anti-angiogenic state
is studied in more detail.
Since we are specifically interested in the therapeutic potential of H2S in a pregnancy-
specific disease, we studied the safety of NaHS treatment in healthy pregnant rats in
Chapter 6. Furthermore, the therapeutic potential of NaHS was evaluated in a pregnant
rat model with sFlt1 overexpression.
Chapter 7 recapitulates the molecular mechanisms by which H2S exerts it vasodilatory
and pro-angiogenic functions, while H2S-based therapies for PE and other cardiovascular
diseases are summarized.
In the final chapter of this thesis, Chapter 8, all findings are summarized and discussed.
Furthermore, future research possibilities to increase the knowledge on the role of H2S in
the pathophysiology and to test its therapeutic potential will be discussed.
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General Introduction | 19
References
1. Bell MJ. a historical overview of preeclampsia-eclampsia. J. Obstet. Gynecol. neonatal nurs. 2010;39(5):510-518.
2. Booth J. a short history of blood pressure measurement. Proc. r. soc. Med. 1977;70(11):793-799.
3. Chesley lC. History and epidemiology of preeclampsia-eclampsia. Clin. Obstet. Gynecol. 1984;27(4):801-820.
4. duley l. the global impact of pre-eclampsia and eclampsia. semin. Perinatol. 2009;33(3):130-137.
5. sibai B, dekker G, Kupferminc M. Pre-eclampsia. lancet 2005;365(9461):785-799.
6. steegers eaP, von dadelszen P, duvekot JJ, Pijnenborg r. Pre-eclampsia. lancet. 2010;376(9741):631-644.
7. Brown Ma, lindheimer Md, de swiet M, Van assche a, Moutquin JM. the classification and diagnosis of the hypertensive disorders of pregnancy: statement from the International society for the study of Hypertension in Pregnancy (IssHP). Hypertens. Pregnancy Off. J. Int. soc. study Hypertens. Pregnancy 2001;20(1):IX-XIV.
8. stillman Ie, Karumanchi sa. the glomerular injury of preeclampsia. J. am. soc. nephrol. 2007;18(8):2281-2284.
9. staff aC, Benton sJ, von dadelszen P, et al. redefining preeclampsia using placenta-derived biomarkers. Hypertension. 2013;61(5):932-942.
10. redman CW, sargent Il. latest advances in understanding preeclampsia. science. 2005;308(5728):1592-1594.
11. levine rJ, Karumanchi sa. Circulating angiogenic factors in preeclampsia. Clin. Obstet. Gynecol. 2005;48(2):372-386.
12. staff aC, Johnsen GM, dechend r, redman CWG. Preeclampsia and uteroplacental acute atherosis: immune and inflammatory factors. J. reprod. Immunol. 2014;101-102:120-126.
13. redman CW, sargent Il, staff aC. IFPa senior award lecture: making sense of pre-eclampsia - two placental causes of preeclampsia? Placenta. 2014;35 suppl:s20-25.
14. roberts JM, taylor rn, Musci tJ, rodgers GM, Hubel Ca, Mclaughlin MK. Preeclampsia: an endothelial cell disorder. am. J. Obstet. Gynecol. 1989;161(5):1200-1204.
15. Kendall rl, thomas Ka. Inhibition of vascular endothelial cell growth factor activity by an endogenously encoded soluble receptor. Proc. natl. acad. sci. u. s. a. 1993;90(22):10705-10709.
16. levine rJ, Maynard se, Qian C, et al. Circulating angiogenic factors and the risk of preeclampsia. n. engl. J. Med. 2004;350(7):672-683.
17. Maynard se, Min J-Y, Merchan J, et al. excess placental soluble fms-like tyrosine kinase 1 (sFlt1) may contribute to endothelial dysfunction, hypertension, and proteinuria in preeclampsia. J. Clin. Invest. 2003;111(5):649-658.
18. Conrad KP, Miles tM, Benyo dF. Circulating levels of Immunoreactive Cytokines in Women with Preeclampsia. am. J. reprod. Immunol. 1998;40(2):102–111.
19. Knight M, redman CW, linton ea, sargent Il. shedding of syncytiotrophoblast microvilli into the maternal circulation in pre-eclamptic pregnancies. Br. J. Obstet. Gynaecol. 1998;105(6):632-640.
20. redman CWG, sargent Il. Circulating microparticles in normal pregnancy and pre-eclampsia. Placenta. 2008;29 suppl a:s73-77.
21. Meher s, duley l. nitric oxide for preventing pre-eclampsia and its complications. Cochrane database syst. rev. Online 2007;(2):Cd006490.
22. Meher s, duley l. rest during pregnancy for preventing pre-eclampsia and its complications in women with normal blood pressure. Cochrane database syst. rev. 2006;(2):Cd005939.
23. roberts JM, Myatt l, spong CY, et al. Vitamins C and e to prevent complications of pregnancy-associated hypertension. n. engl. J. Med. 2010;362(14):1282-1291.
24. Hofmeyr GJ, lawrie ta, atallah an, duley l, torloni Mr. Calcium supplementation during pregnancy for preventing hypertensive disorders and related problems. Cochrane database syst. rev. 2014;6:Cd001059.
25. Henderson Jt, Whitlock eP, O’Connor e, senger Ca, thompson JH, rowland MG. low-dose aspirin for prevention of morbidity and mortality from preeclampsia: a systematic evidence review for the u.s. Preventive services task Force. ann. Intern. Med. 2014;160(10):695-703.
26. Bergmann a, ahmad s, Cudmore M, et al. reduction of circulating soluble Flt-1 alleviates preeclampsia-like symptoms in a mouse model. J. Cell. Mol. Med. 2010;14(6B):1857-1867.
27. Gilbert Js, Verzwyvelt J, Colson d, arany M, Karumanchi sa, Granger JP. recombinant vascular endothelial growth factor 121 infusion lowers blood pressure and improves renal function in rats with placentalischemia-induced hypertension. Hypertension. 2010;55(2):380-385.
28. li Z, Zhang Y, Ying Ma J, et al. recombinant vascular endothelial growth factor 121 attenuates hypertension and improves kidney damage in a rat model of preeclampsia. Hypertension. 2007;50(4):686-692.
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20 | Chapter One
29. thadhani r, Kisner t, Hagmann H, et al. Pilot study of extracorporeal removal of soluble fms-like tyrosine kinase 1 in preeclampsia. Circulation. 2011;124(8):940-950.
30. Wang r. two’s company, three’s a crowd: can H2s be the third endogenous gaseous transmitter? FaseB J. Off. Publ. Fed. am. soc. exp. Biol. 2002;16(13):1792-1798.
31. li l, Hsu a, Moore PK. actions and interactions of nitric oxide, carbon monoxide and hydrogen sulphide in the cardiovascular system and in inflammation--a tale of three gases! Pharmacol. ther. 2009;123(3):386-400.
32. lópez-Jaramillo P, arenas Wd, García rG, rincon MY, lópez M. the role of the l-arginine-nitric oxide pathway in preeclampsia. ther. adv. Cardiovasc. dis. 2008;2(4):261-275.
33. Zhao H, Wong rJ, doyle tC, et al. regulation of maternal and fetal hemodynamics by heme oxygenase in mice. Biol. reprod. 2008;78(4):744-751.
34. Baum M, schiff e, Kreiser d, et al. end-tidal carbon monoxide measurements in women with pregnancy-induced hypertension and preeclampsia. am. J. Obstet. Gynecol. 2000;183(4):900-903.
35. savvidou Md, Hingorani ad, tsikas d, Frölich JC, Vallance P, nicolaides KH. endothelial dysfunction and raised plasma concentrations of asymmetric dimethylarginine in pregnant women who subsequently develop pre-eclampsia. lancet. 2003;361(9368):1511-1517.
36. Cudmore M, ahmad s, al-ani B, et al. negative regulation of soluble Flt-1 and soluble endoglin release by heme oxygenase-1. Circulation. 2007;115(13):1789-1797.
37. Groesch Ka, torry rJ, Wilber aC, et al. nitric oxide generation affects pro- and anti-angiogenic growth factor expression in primary human trophoblast. Placenta. 2011;32(12):926-931.
38. li F, Hagaman Jr, Kim H-s, et al. enOs deficiency acts through endothelin to aggravate sFlt-1-Induced Pre-eclampsia-like Phenotype. J. am. soc. nephrol. 2012;23(4):652-60.
39. eide IP, Isaksen CV, salvesen Ka, langaas M, schønberg sa, austgulen r. decidual expression and maternal serum levels of heme oxygenase 1 are increased in pre-eclampsia. acta Obstet. Gynecol. scand. 2008;87(3):272-279.
40. dorniak-Wall t, Grivell rM, dekker Ga, Hague W, dodd JM. the role of l-arginine in the prevention and treatment of pre-eclampsia: a systematic review of randomised trials. J. Hum. Hypertens. 2014;28(4):230-235.
41. ahmed a. new insights into the etiology of preeclampsia: identification of key elusive factors for the vascular complications. thromb. res. 2011;127 suppl 3:s72-75.
42. McGuane Jt, debrah Je, sautina l, et al. relaxin induces rapid dilation of rodent small renal and human subcutaneous arteries via PI3 kinase and nitric oxide. endocrinology. 2011;152(7):2786-2796.
43. unemori e, sibai B, teichman sl. scientific rationale and design of a phase I safety study of relaxin in women with severe preeclampsia. ann. n. Y. acad. sci. 2009;1160:381-384.
44. ramma W, ahmed a. therapeutic potential of statins and the induction of heme oxygenase-1 in preeclampsia. J. reprod. Immunol. 2014;101-102:153-160.
45. Zhao W, Zhang J, lu Y, Wang r. the vasorelaxant effect of H(2)s as a novel endogenous gaseous K(atP) channel opener. eMBO J. 2001;20(21):6008-6016.
46. shibuya n, Mikami Y, Kimura Y, nagahara n, Kimura H. Vascular endothelium expresses 3-mercaptopyruvate sulfurtransferase and produces hydrogen sulfide. J. Biochem. (tokyo) 2009;146(5):623-626.
47. stipanuk MH, ueki I. dealing with methionine/homocysteine sulfur: cysteine metabolism to taurine and inorganic sulfur. J. Inherit. Metab. dis. 2011;34(1):17-32.
48. Bos eM, van Goor H, Joles Ja, Whiteman M, leuvenink HGd. Hydrogen sulfide: physiological properties and therapeutic potential in ischaemia. Br. J. Pharmacol. 2015;172(6):1479-1493.
49. Yang G, Wu l, Jiang B, et al. H2s as a physiologic vasorelaxant: hypertension in mice with deletion of cystathionine gamma-lyase. science. 2008;322(5901):587-590.
50. sen u, Munjal C, Qipshidze n, abe O, Gargoum r, tyagi sC. Hydrogen sulfide regulates homocysteine-mediated glomerulosclerosis. am. J. nephrol. 2010;31(5):442-455.
51. Miles eW, Kraus JP. Cystathionine beta-synthase: structure, function, regulation, and location of homocystinuria-causing mutations. J. Biol. Chem. 2004;279(29):29871-29874.
52. Wilson KM, lentz sr. Mechanisms of the atherogenic effects of elevated homocysteine in experimental models. semin. Vasc. Med. 2005;5(2):163-171.
53. Jackson-Weaver O, Paredes da, Gonzalez Bosc lV, Walker Br, Kanagy nl. Intermittent hypoxia in rats increases myogenic tone through loss of hydrogen sulfide activation of large-conductance Ca(2+)-activated potassium channels. Circ. res. 2011;108(12): 1439-1447.
54. tang G, Yang G, Jiang B, Ju Y, Wu l, Wang r. H2s is an endothelium-derived hyperpolarizing factor. antioxid. redox signal. 2013;19(14):1634-1646.
55. Mustafa aK, sikka G, Gazi sK, et al. Hydrogen sulfide as endothelium-derived hyperpolarizing factor sulfhydrates
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potassium channels. Circ. res. 2011;109(11):1259-1268.
56. Coletta C, Papapetropoulos a, erdelyi K, et al. Hydrogen sulfide and nitric oxide are mutually dependent in the regulation of angiogenesis and endothelium-dependent vasorelaxation. Proc. natl. acad. sci. u. s. a. 2012;109(23):9161-6.
57. lu M, liu Y-H, Goh Hs, et al. Hydrogen sulfide inhibits plasma renin activity. J. am. soc. nephrol. Jasn 2010;21(6):993-1002.
58. Cai W-J, Wang M-J, Moore PK, Jin H-M, Yao t, Zhu Y-C. the novel Proangiogenic effect of Hydrogen sulfide Is dependent on akt Phosphorylation. Cardiovasc. res. 2007;76(1):29-40.
59. Papapetropoulos a, Pyriochou a, altaany Z, et al. Hydrogen sulfide is an endogenous stimulator of angiogenesis. Proc. natl. acad. sci. u. s. a. 2009;106(51):21972-21977.
60. Wang M-J, Cai W-J, li n, ding Y-J, Chen Y, Zhu Y-C. the hydrogen sulfide donor naHs promotes angiogenesis in a rat model of hind limb ischemia. antioxid. redox signal. 2010;12(9):1065-1077.
61. Kondo K, Bhushan s, King al, et al. H2s protects against pressure overload-induced heart failure via upregulation of endothelial nitric oxide synthase. Circulation. 2013;127(10):1116-1127.
62. Polhemus dJ, Kondo K, Bhushan s, et al. Hydrogen sulfide attenuates cardiac dysfunction after heart failure via induction of angiogenesis. Circ. Heart Fail. 2013;6(5):1077-1086.
63. tao B-B, liu s-Y, Zhang C-C, et al. VeGFr2 Functions as an H(2)s-targeting receptor Protein Kinase with Its novel Cys1045-Cys1024 disulfide Bond serving as a specific Molecular switch for Hydrogen sulfide actions in Vascular endothelial Cells. antioxid. redox signal. 2013;19(5):448-64.
64. altaany Z, Moccia F, Munaron l, Mancardi d, Wang r. Hydrogen sulfide and endothelial dysfunction: relationship with nitric Oxide. Curr. Med. Chem. 2014;21(32):3646-61.
65. Predmore Bl, lefer dJ. development of hydrogen sulfide-based therapeutics for cardiovascular disease. J Cardiovasc. transl. res. 2010;3(5): 487-498.
66. Zanardo rCO, Brancaleone V, distrutti e, Fiorucci s, Cirino G, Wallace Jl. Hydrogen sulfide is an endogenous modulator of leukocyte-mediated inflammation. FaseB J. Off. Publ. Fed. am. soc. exp. Biol. 2006;20(12):2118-2120.
67. li l, Whiteman M, Guan YY, et al. Characterization of a novel, water-soluble hydrogen sulfide-releasing molecule (GYY4137): new insights into the biology of hydrogen sulfide. Circulation 2008;117(18):2351-2360.
68. Kan J, Guo W, Huang C, Bao G, Zhu Y, Zhu YZ. s-propargyl-cysteine, a novel water-soluble modulator of endogenous hydrogen sulfide, promotes angiogenesis through activation of signal transducer and activator of transcription 3. antioxid. redox signal. 2014;20(15):2303-2316.
69. snijder PM, Frenay as, de Boer ra, et al. exogenous administration of thiosulfate, a donor of hydrogen sulfide, attenuates angiotensin II-induced hypertensive heart disease in rats. Br. J. Pharmacol. 2015;172(6):1494-504.
70. Patel P, Vatish M, Heptinstall J, Wang r, Carson rJ. the endogenous production of hydrogen sulphide in intrauterine tissues. reprod. Biol. endocrinol. 2009;7:10.
71. Mislanova C, Martsenyuk O, Huppertz B, Obolenskaya M. Placental markers of folate-related metabolism in preeclampsia. reprod. Camb. engl. 2011;142(3):467-476.
72. Cindrova-davies t, Herrera ea, niu Y, Kingdom J, Giussani da, Burton GJ. reduced Cystathionine γ-lyase and Increased Microrna-21 expression are associated with Increased Vascular resistance in Growth-restricted Pregnancies: Hydrogen sulfide as a Placental Vasodilator. am J Pathol. 2013 apr;182(4):1448-58.
73. solanky n, requena Jimenez a, d’souza sW, sibley CP, Glazier Jd. expression of folate transporters in human placenta and implications for homocysteine metabolism. Placenta. 2010;31(2):134-143.
74. Braekke K, ueland PM, Harsem nK, Karlsen a, Blomhoff r, staff aC. Homocysteine, Cysteine, and re-lated Metabolites in Maternal and Fetal Plasma in Preeclampsia. Pediatr. res. 2007;62(3):319-324.
75. el-Khairy l, Vollset se, refsum H, ueland PM. Plasma total cysteine, pregnancy complications, and adverse pregnancy outcomes: the Hordaland Homocysteine study. am. J. Clin. nutr. 2003;77(2):467-472.
76. Powers rW, evans rW, Majors aK, et al. Plasma homocysteine concentration is increased in pre-eclampsia and is associated with evidence of endothelial activation. am. J. Obstet. Gynecol. 1998;179(6 Pt 1):1605-1611.
77. Malinow Mr, rajkovic a, duell PB, Hess dl, upson BM. the relation-ship between maternal and neonatal umbilical cord plasma homo-cyst(e)ine suggests a potential role for maternal homocyst(e)ine in fetal metabolism. am. J. Obstet. Gynecol. 1998;178(2):228-233.
78. Murphy MM, scott JM, arija V, Molloy aM, Fernandez-Ballart Jd. Maternal homocysteine before con-ception and throughout pregnancy predicts fetal homocysteine and birth weight. Clin. Chem. 2004;50(8): 1406-1412.
79. Powers rW, Gandley re, lykins dl, roberts JM. Moderate hyper-homocysteinemia decreases endo-thelial-dependent vasorelaxation in pregnant but not nonpregnant mice. Hypertension. 2004;44(3):327-333.
80. nuño-ayala M, Guillén n, arnal C, et al. Cystathionine-γ-synthase deficiency causes infertility by impairing decidualization and gene expression networks in uterus implantation sites. Physiol. Genomics 2012;44(14):702-716.
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Pa r t IHuman studies
Hydrogen sulfide in the pathophysiology of preeclampsia
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