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University of Groningen

Hydrogen Sulfide in PreeclampsiaHolwerda, Kim

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Ch a pte r 1General Introduction


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


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


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



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).


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.



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


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



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.


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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20 | Chapter One

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