Hypertension in Pregnancy

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Linking the old and new — do angiotensin II type 1

receptor antibodies provide the missing link in the
pathophysiology of preeclampsia?

Shikha Aggarwal, Angela Makris & Annemarie Hennessy

To cite this article: Shikha Aggarwal, Angela Makris & Annemarie Hennessy (2015) Linking
the old and new — do angiotensin II type 1 receptor antibodies provide the missing link
in the pathophysiology of preeclampsia?, Hypertension in Pregnancy, 34:3, 369-382, DOI:
10.3109/10641955.2015.1051227

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Hypertens Pregnancy, 2015; 34(3): 369–382
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ISSN: 1064-1955 print / 1525-6065 online
DOI: 10.3109/10641955.2015.1051227

Linking the old and new — do

angiotensin II type 1 receptor antibodies
provide the missing link in the
pathophysiology of preeclampsia?
Shikha Aggarwal,1,2 Angela Makris,1,2,3 and Annemarie
Hennessy1,2,4
1
School of Medicine, University of Western Sydney, NSW, Australia,
2
Vascular Immunology Laboratory, Heart Research Institute, NSW, Australia,
3
Department of Renal Medicine, Liverpool Hospital, UNSW, Australia, and
4
Department of Renal Medicine, Campbelltown Hospital, NSW, Australia

Preeclampsia remains a leading cause of maternal and neonatal morbidity and

mortality. The pathophysiology of preeclampsia remains poorly understood with various
pathological mechanisms being implicated including the renin angiotensin system
(RAAS), angiogenic pathways and various components of the immune system. Recently
a pathogenic autoimmune factor has been identified in the form of auto-agonistic
angiotensin II type 1 receptor antibodies (AT1-AA). AT1-AA have been studied in vitro
and in vivo in various human and animal models and these data have provided
compelling evidence for their role in preeclampsia. This review summarises the current
literature surrounding the role of AT1-AA in preeclampsia and draws links between
this relatively novel antibody to well-established pathological mechanisms including
the immune system, the RAAS, angiogenic pathways and placental ischaemia.

Keywords Angiotensin II type 1 receptor antibodies, placenta, preeclampsia.

INTRODUCTION
Preeclampsia affects 3–5% of all pregnancies and remains a leading cause of
maternal and neonatal morbidity and mortality (1). The clinical hallmarks of
the disease include the onset of hypertension after 20 weeks of gestation
associated with proteinuria, renal failure, elevated liver enzymes with low
platelets (HELLP syndrome) and cerebral oedema with seizures (2).
Due to the limited understanding of the disease process and unreliable
diagnostic techniques, current therapeutic options are limited (2). Treatment
options involve managing the hypertension and as the disease progresses,
delivering the baby and placenta to prevent further deterioration of the mother
and baby, even if premature. Preeclampsia is not a benign disorder and the
consequences do not end with pregnancy as previously thought (3). Studies of
long-term health outcomes in women who develop preeclampsia have shown

Correspondence: Shikha Aggarwal, School of Medicine, University of Western Sydney,

Campbelltown, NSW, Australia. E-mail: dr.saggarwal85@gmail.com
370 S. Aggarwal et al.

that both women (4) and their babies (5) are at increased risk of cardiovascular
disorders later in life. Furthermore it is associated with significant morbidity
to the neonates, accounting for up to 15% of pre-term births (1).
Preeclampsia is considered a maternal endothelial disorder made up of two
stages (6). The first stage occurs when there is abnormal placental implant-
ation secondary to insufficient invasion of the maternal uterine spiral arteries
by trophoblast cells (7). This results in impaired placental blood flow and
development. The second stage of the disease comprises of the ischaemic and or
reperfusion phenomena associated with a hypoxic placenta, which releases
circulating factors into the maternal circulation (8). These circulating factors
and other tissue-based pathways such as free radical generation contribute
to the clinical features of preeclampsia via alterations in endothelial cell
function (9). The circulating factors include inflammatory cytokines (10), e.g.
TNF-a (tumour necrosis factor- alpha), IL-6 (interleukin-6) and angiogenic
molecules such as soluble endogolin (sEng) (11) and soluble fms-like tyrosine
kinase 1 receptor (sFlt-1) (12). These factors have not only been shown to be
elevated in preeclamptic women but have also been shown to be a response to
placental ischaemia (10,12,13) thus making the link between clinical disease
and putative mechanism of placental ischaemia.
Alterations in the renin- angiotensin- aldosterone system (RAAS) have also
been shown to be substantially different in preeclampsia compared with
normal pregnancy (14). Whether these differences indicate a critical role in the
pathophysiology of preeclampsia remains uncertain and targeting the RAAS
has not afforded any therapeutic interventions for either placental function or
clinical disease to date. Given our recent and improved understanding about
the links between blood flow/hypoxia, placental protein synthesis and mater-
nal disease, it is timely to consider how differences in elements of the RAAS
and its regulation align with these disease mechanisms.
More recently an autoimmune factor has been identified: angiotensin II type
1-receptor autoantibodies (AT1-AA) that may have a role in the underlying
pathogenesis in women with preeclampsia (15). The generation of these
autoantibodies in women with preeclampsia, would potentially link the
various known aspects of disease pathology: immune system involvement
and antiangiogenic pathways with the RAAS.
This review discusses the role of AT1-AA in preeclampsia and it’s relation to
the other pathological mechanisms of the disease. It aims to explore the link
between AT1-AA and other immune markers, antiangiogenic pathways the
RAAS and tie all of these together to the concept of ischaemia and even
reperfusion injury and placental hypoxia.

AT1-AA
AT1-AA were first described in preeclampsia by Wallukat et al. (15). The group
detected the stimulatory effect of AT1-AA in the sera of preeclamptic women
using neonatal rat cardiomyocyte contraction assays. Wallukat et al. (16) have
also shown the agonistic antibody to be an immunoglobulin G (IgG) of the IgG3
subclass. These antibodies are directed to a specific epitope on the second
extracellular loop on the angiotensin II type 1 (AT1) receptor and bind
to receptors found in/on human trophoblasts and vascular cells (17).
 The role of AT1-AA in preeclampsia 371

AT1 receptors and angiotensin 2 (AT2) receptors are the two major receptors
for angiotensin and belong to a family of seven transmembrane G protein
coupled receptors (14). AT1 receptors are expressed on vascular smooth
muscles and adrenal glands and are coupled to the Gq protein and stimulate
intracellular calcium release (14). They are responsible for the majority of
angiotensin II mediated effects such as vasoconstriction, sympathetic activity
and release of Aldosterone (14). AT2 receptors are widely expressed in fetal
tissue and have limited expression in adult tissue (they will not be discussed
further in this review).
Following these initial studies, multiple in-vitro laboratory studies have
shown mechanistic pathways for the involvement of AT1-AA in women with
preeclampsia.

 AT1-AA from preeclamptic women have been shown to induce vasocon-

striction in rat thoracic aorta, arteriae cerebri media and coronary arteries
by activating AT1 receptors on vascular smooth muscles (18). AT1-AA
have also been shown to induce vasoconstriction through activation of
Endothelin 1 (ET-1) and the endothelin pathway in a rat animal model
(19). Activation of endothelin receptors (Eta) by ET-1 has been shown to
attenuate the clinical symptoms of preeclampsia (20). These results
indicate that AT1-AA may play a causative role in the development of
hypertension in preeclampsia.
 AT1-AA from preeclamptic women induced endothelial cell vasoconstric-
tion in a dose dependant manner in rat thoracic aorta (21). Furthermore
they have also been shown to induce endothelial cell death by necrosis and
apoptosis in human umbilical vein endothelial cells (HUVECS) supporting
the direct involvement of AT1-AA in endothelial damage.
 AT1-AA stimulate tissue factor production contributing to hypercoagula-
tion through activation of vascular smooth muscle cells in human coronary
arteries (22). Tissue factor expression has also been shown in preeclamptic
placentas (22) indicating another potential pathway for AT1-AA function
in the pathogenesis of preeclampsia.
 AT1-AA contribute to decreased fibrinolysis and less extracellular matrix
degradation by increasing PAI-1 (plasminogen- activator inhibitor-1)
production in human mesangial cells (23). This mechanism may be
responsible for some of the renal manifestations seen in preeclampsia.
PAI-1 gene expression has been shown to be increased by downstream
calcium-dependent calcineurin- nuclear factor of activated T cells (NFAT)
signaling pathways following AT1 receptor activation by AT1-AA (24). AT1
receptor activation by this pathway has been shown to decrease tropho-
blast invasion in human cell culture models (24) indicating a potential
pathway for AT1-AA involvement in stage 1 of preeclampsia pathogenesis.
 AT1-AA contribute to the production of reactive oxygen species (ROS)
through nicotinamide adenine dinucleotide phosphate-oxidase (NADPH
oxidase) activation in cell culture models (25). Excessive ROS has been
postulated to play a role in aberrant placentation.
 ATI-AA have also been shown to stimulate intracellular calcium release
from vascular smooth muscle cells via AT1 receptor activation (26). This
may provide a causal relationship with the increased intracellular calcium
372 S. Aggarwal et al.

seen in a variety of cell types (platelets, erythrocytes, lymphocytes) in

preeclamptic women (27–29).

AT1-AA AND HUMAN STUDIES

Siddiqui et al. (30) showed that AT1-AA were present in greater than 95% of
the women with preeclampsia and in less than 30% of normotensive women.
They also showed that the higher titres of antibody (measured by percentage
increase of luciferase activity over basal activity using a Promega luciferase
assay kit) correlated with disease severity. Although AT1-AA levels have been
shown to decline by 50% 1 week postpartum (15) more recently Hubel et al.
(31) have reported that 17.9% of women with preeclampsia compared to 2.9%
of normal pregnant women still harboured AT1-AA 18±9 months post partum.
Irani et al. (32) have shown the presence of AT1-AA in cord blood of
pregnant women and using antibody transfer models they have shown that
AT1-AA can cross the placenta. The group showed that by crossing the
fetomaternal junction these antibodies can enter fetal circulation and are
associated with fetal growth restriction and hepatic and renal abnormalities.
More recently Zhang et al. (33) have demonstrated that AT1-AA in
preeclamptic sera can directly constrict fetoplacental villus blood vessels
(shown in human placental explants) which may contribute to poor
fetoplacental perfusion and hence intrauterine growth restriction (IUGR) in
preeclampsia.
Other studies have suggested that AT1-AA can be detected as early as
18 weeks gestation in human pregnancy prior to the development of clinical
preeclampsia (34) indicating that the antibodies are a mediator of early disease
as opposed to late onset disease. This data is different to the experiments
conducted by Herse et al. (35) who demonstrated that AT1-AA were more
predictive in late gestation and hence a better marker for late disease.
Although these data provide a role for AT1-AA in clinical manifestation of
preeclampsia, studies outside of pregnancy indicate that these antibodies are
not specific for preeclampsia. These antibodies have been identified in patients
with vascular rejection post renal transplantation (36), in patients with
malignant hypertension (37) and more recently in patients with other
autoimmune disorders such as systemic sclerosis (38) and lupus nephritis (39).

AT1-AA AND ANIMAL MODELS

Zhou et al. (40) went on to describe that the key features of preeclampsia,
including hypertension, proteinuria, histopathological renal damage consist-
ent with preeclampsia, placental abnormalities and small foetus size were
induced in pregnant mice after an injection of total IgG and affinity purified
AT1-AA from women with preeclampsia. IgG was introduced into pregnant
mice at day 13, the timing of which approximates early onset preeclampsia in
humans. The same group also showed that this syndrome induced by AT1-AA
was reversible with the administration of losartan (AT1 receptor antagonist)
therapy. They also described the preventable nature of the clinical features
when a seven- amino acid epitope peptide (which has been shown to block AT1
 The role of AT1-AA in preeclampsia 373

receptor activation by AT-1-AA) is present. These results demonstrated that in

these mice, the clinical features described were driven by AT1 receptor
activation by biologically active autoantibodies. Furthermore, Takeda-
Matsubara et al. (41) have shown that blood pressure was significantly
reduced in second trimester AT1 receptor null pregnant mice. This data
demonstrate that the activation of AT1 receptors by AT1-AA may be a
contributing factor of the hypertension seen in preeclampsia.
Irani et al. (32) have shown that AT1-AA can induce apoptosis in placentas
of pregnant mice. They also showed that placental apoptosis was ameliorated
by administration of losartan or a seven- amino acid epitope peptide.
Furthermore the pups of mice with injected AT1-AA and placental ischaemia
were small and showed delayed organ maturation. They were able to replicate
some of these results in human villous explants and cultured human
trophoblasts. These studies further delineate the important role of AT1-AA
in placental damage.
These animal studies, in conjunction with the human data, provide in vivo
experimental evidence for the hypothesis that preeclampsia is an immune
driven process and that this autoimmunity may not end with pregnancy. The
AT1-AA provide a link between various components of preeclampsia patho-
genesis (Figure 1).

Figure 1. Linking the multifactorial aspects of the pathogenesis of preeclampsia:

placental ischaemia induces AT1-AA production. AT1-AA stimulates the immune
system, both innate and adaptive. The immune system further contributes to placental
ischaemia creating a vicious cycle of inflammation. The adaptive component of the
immune system predominantly the B cells are responsible for production of AT1-AA,
hence feedback into antibody production. AT1-AA stimulates the anti-angiogenic
pathways, which manifest as clinical features of preeclampsia. AT1-AA down regulates
the RAAS, renin and angiotensin possibly through negative feedback and aldosterone
by decreasing adrenal blood flow. How the RAAS then links with placental ischaemia
remains uncertain.
374 S. Aggarwal et al.

AT1-AA AND PLACENTAL ISCHAEMIA

Granger et al. (42) have demonstrated that a preeclampsia like syndrome can
be replicated in rats by surgically inducing placental ischaemia. This model is
known as the reduced uterine perfusion pressure (RUPP) model. LaMarca
et al. have also shown that TNF-a (43) and IL-6 (44) are elevated in this RUPP
model and infusions of these cytokines into pregnant rats results in hyper-
tension and reduced glomerular function. They have also shown that in RUPP
rats, IL-6 regulates the induction of ET-1 from endothelial cells contributing to
hypertension (45). More recently the same group have demonstrated that
AT1-AA are also present in the RUPP model and can be induced by TNF-a (46)
and IL-6 (44) infusions. These animal models show that hypoxia/ischaemia and
inflammtion can induce AT1-AA.
Walther et al. (34) have similarly shown that AT1-AA can be detected in
pregnancies with impaired placental development. The group used Doppler
ultrasonography to identify patients with abnormal uterine perfusion and used
this as a surrogate marker for inadequate trophoblast invasion and hence
increased likelihood of developing preeclampsia. They demonstrated that
AT1-AA were present in 80% of the second trimester women with abnormal
uterine perfusion who went on to develop preeclampsia. They also showed that
the antibody was present in women with abnormal uterine perfusion who later
developed IUGR (60%) or normal deliveries (62%). Furthermore, in the third
trimester the antibody was present in 89% and 86% of women with
preeclampsia or IUGR, respectively.

AT1-AA AND THE IMMUNE SYSTEM

There is an exaggerated inflammatory response mediated by both the innate
and adaptive immune systems in preeclampsia. Immunological changes in the
early placental microenvironment have been suggested to play a role in the
origin of preeclampsia or stage 1 of disease. Abnormal trophoblast invasion is
thought to be secondary to alterations in the interaction between decidual
natural killer cells and decreased human leucocyte antigen-G complexes in
preeclampsia (47). This altered interaction promotes the production of pro-
inflammatory cytokines and angiogenic factors. In stage 2 of disease,
persistent placental hypoxia and changes in oxygen sensing mechanisms
promote ongoing inflammation amongst other things.

Innate Immune System

The maternal inflammatory process is thought to be triggered by activation of
toll like receptors (48) by the release of syncitiotrophblast micro-particles
(STBM), free foetal DNA and damage associated molecular patterns (DAMPs)
into the maternal circulation (47). In normal pregnancy, STBMs contribute to
anti-inflammatory pathways by inhibiting IFN-g production and promoting a
shift towards T helper cells type 2 (Th-2) like responses. These STBMs are
increased in preeclampsia compared to normal pregnancy (49) and result in
stimulation of monocytes (50), neutrophils (51), natural killer cells (52) and
dendritic cells. They contribute to the pro-inflammatory state by activating
monocytes to release cytokines (53) such as IFN-g, TNF-a, IL-18 and IL-12.
 The role of AT1-AA in preeclampsia 375

Activation of neutrophils promotes vascular dysfunction through the processes

of elastase release, neutrophil extracellular traps (NETS) formation and
superoxide related damage (54). Changes in dendritic cell subtypes may
modulate the adaptive immune system by promoting a shift towards the Th-1
(T helper cells type 1) response type (55).
Research groups have shown that cytokine injections of TNF-a (56), IL-6
(44) and IL-17 (57) can cause clinical features of preeclampsia such as
proteinuria and hypertension in pregnant rodents. Alternatively injection of
AT1-AA into pregnant mice can induce downstream signalling of TNF-a (58)
and IL-6 (23). By blocking TNF-a in mice with a neutralising antibody these
clinical features (proteinuria and hypertension) along with signalling of IL-6,
sFlt-1 and sEng were ameliorated (59).

Adaptive Immune System

In normal pregnancy there is a shift from pro-inflammatory responses
mediated by Th-1 to anti-inflammatory responses mediated by Th-2 in order
to protect the foetus from a maternal cell-mediated immune attack. In
preeclampsia this shift does not occur and is associated with a greater
Th-1 mediated cytokine response (60) arising from the placenta. High levels
of IFN-g and low levels of IL-10 may promote the production of Th-1
lymphocytes (61).
CD4 lymphocyte subsets that have been shown to play a role in
preeclampsia include regulatory T cells (Tregs) and Th-17 T cells. Th-17 cells
secrete IL-17 and play an important role in autoimmune disorders and chronic
inflammatory states such as lupus. In preeclampsia, Treg function is reduced
due to decreased mRNA of FOXP3 whilst TH-17 cells are predominant as a
result of increased Th-17 transcription factor RORc (retinoid-related orphan
receptor C) (53,62). This change in Th-17:Treg ratio may be a contributing
factor to the inflammatory process in preeclampsia.
Jensen et al. (63) have shown that specific B cell populations are responsible
for the production of AT1-AA. These populations are the CD19 (+)CD5 (+) cell
types and have been shown to be present in preeclamptic placentas and not in
normal pregnancies. B lymphocyte depletion with CD20 blockade in the RUPP
rat model has shown to suppress AT1-AA secretion (64) revealing B cell
suppression, as a potential therapeutic target – however there was no
assessment of improvement of clinically important features e.g. hypertension
or proteinuria. IL-6 has been shown to be a stimulus for B cells to produce
AT1-AA (44) but the specific antigen-activating AT1-AA production initially
remains unknown.

AT1-AA AND ANTI-ANGIOGENIC PATHWAYS

In preeclampsia there is an imbalance between pro-angiogenic and anti-
angiogenic pathways – the precise mechanisms behind these remain uncer-
tain, although placental hypoxia and more recently AT1-AA have been
implicated.
Vascular endothelial growth factor (VEGF) and placental growth factor
(PlGF) promote angiogenesis through their receptor fms-like tyrosine kinase-1
(FLT-1). sFLT-1 is a circulating soluble isoform of the VEGF receptor that has
376 S. Aggarwal et al.

anti-angiogenic properties. sFLT-1 binds free VEGF and PlGF preventing

further binding to their transmembrane receptor and thus inhibiting their
biological action. Maynard et al. (12) showed higher circulating concentrations
and placental expression of sFLT-1 in women with preeclampsia compared to
normal pregnancy. Furthermore, the rise in sFLT-1 was shown to be a response
to placental ischaemia (13) and consequently the up-regulation of hypoxia-
inducible factor 1-alpha (65). Studies have shown that AT1-AA stimulates the
production of sFlt-1 from human trophoblasts (in cell culture) and placental
explants through TNF-a pathways and downstream signalling of calcineurin
and nuclear factor of activated T cells (NFAT) (40). By infusing recombinant
VEGF into autoantibody infused pregnant mice the effects of hypertension and
proteinuria are ameliorated (66). These studies indicate that sFlt-1 is a key
factor by which AT1-AA exert their biological effects.
Venkatesha et al. (11) have shown that soluble endogolin (sEng) is a
placenta-derived soluble receptor for transforming growth factor beta (TGF-b1
and TGF-b3), which is elevated in preeclampsia and correlates with disease
severity. sEng is expressed on endothelial cells and syncitiotrophoblasts and
interferes with TGF- b binding and downstream signalling of nitric oxide and
vasodilation. Also, sEng induces vascular permeability and hypertension
in vivo and when combined with sFlt-1 leads to the HELLP syndrome. More
recently Zhou et al. (59) have shown that AT1-AA are responsible for sEng
induction via TNF-a signalling in mouse models. These studies demonstrate a
further antiangiogenic pathway in which AT1-AA may have a role.

AT1-AA AND THE RAAS

Pregnancy is a hyper-dynamic state in which there is a 30–40% increase in
plasma volume. This rise in volume is the key factor required to maintain
organ perfusion. In early gestation vasodilators such as nitric oxide decrease
systemic vascular resistance (67) and hence activate the RAAS. The physio-
logical response of the RAAS is to increase renin, angiotensin II and
aldosterone (68). This allows for an aldosterone dependant increase in
plasma volume. The maternal blood pressure however does not increase and
this is thought to be secondary to a relative resistance to the presser response
of angiotensin II (69).
The RAAS is markedly different in preeclampsia compared to normal
pregnancies. The predominant findings are of a reduction in active plasma
renin concentration with a corresponding decrease in concentrations of
plasma angiotensin II and aldosterone (70). These hormone reductions seem
paradoxical in view of the decreased plasma volume that has been identified
in preeclampsia (71). Some possible explanations for the relatively reduced
renin levels include suppression by the elevated atrial natriuretic peptide
(72), increased angiotensin sensitivity and the presence of AT1-AA. Other
placental factors such as VEGF appear to stimulate renin in normal
pregnancy. This is evidenced by the fact that VEGF inhibition by Sunitinib
(multi-targeted tyrosine kinase receptor inhibitor including VEGF) has
shown a decrease renin in non-pregnant rats (73); and in preeclampsia. It
may be that VEGF binding by sFLT-1 may be a contributory factor to low-
renin levels.
 The role of AT1-AA in preeclampsia 377

In preeclampsia women do not have the same resistance to the hypertensive

effects of angiotensin II as in normal pregnancy. Although angiotensin II
concentrations are reduced in preeclampsia, studies have shown that there is
increased presser sensitivity to infused angiotensin II (69). Angiotensin II
exerts its effects through AT1 receptors and an explanation for the vasocon-
striction syndrome despite the relatively lower angiotensin II concentrations
may be the stimulation of AT1 by AT1-AA.
Lower aldosterone levels in preeclampsia may be the cause for the decreased
plasma volume resulting in placental hypoxia. This theory was further
explored by Gennari-Moser et al. (74) who showed that blocking aldosterone
receptors with spironolactone in mice resulted in reduced umbilical flow. In
normal pregnancy, the aldosterone to renin ratio is elevated indicating that
aldosterone production is not solely determined by angiotensin II, studies
have reported independent aldosterone stimulation by VEGF (75). Recently
Sidiqqui et al. (76) have shown that sFLT-1 mediated by AT1-AA can impair
adrenal vasculature directly reducing aldosterone production. Furthermore
they showed this phenomenon could be prevented by infusion of recombinant
VEGF. These mechanisms provide alternate explanations for low-aldosterone
levels in preeclampsia where AT1-AA are elevated and VEGF is inactivated
by sflt-1.

PERSPECTIVES
The current research in humans suggests that maybe these antibodies occur
prior to the development of the preeclampsia syndrome and may be the
initiating factor for the disease. However, the timing and or sequence
relationships between placental hypoxia, inflammatory cytokines, antiangio-
genic molecules such as sFlt-1 and AT1-AA in humans have not been
determined. Causality would be indicated here by looking at the gestational
specific sequence of changes in these molecules in women destined to develop
preeclampsia. Ultimately the ability to correct the AT1-AA at the ‘‘right’’ time
of a pregnancy and then preventing disease would answer the question.
Whether these antibodies affect placental implantation and result in
placental ischaemia remains uncertain. The critical issues here are about
timing, sequence and the actual events going on in the placenta, which we are
unable to measure. Does all reduced blood flow (at all times of pregnancy) lead
to the same level of ischaemic insult? There is clearly a vicious cycle of
placental damage that occurs as both AT1-AA and RUPP lead to markers
of ischaemia and inflammatory stimulation. It is likely that the technical
aspects of animal studies produce a range of placental insults from frank
infarction to ischaemic reperfusion injury and therefore a range of placental
synthetic responses (77).
Furthermore as these antibodies have the potential to explain the RAAS
changes in preeclampsia for the first time, future studies of the links between
RAAS deactivation, plasma vasculature changes and placental blood flow may
well be informed by a more detail assessment of AT1-AA in human and
relevant animals studies.
The key lies in determining the timing of onset of these antibodies and their
downstream effects. Are they detected in serum in time to reverse the
378 S. Aggarwal et al.

syndrome or prevent further deterioration? What management strategies are

available to dampen the effect of these autoantibodies? Whether other current
prophylactic type treatments (e.g. aspirin) have an effect on autoantibody
production (either directly, or via coagulation pathway effects or even via
improving placental blood flow) has not been examined. These questions
remained unanswered and further research is required to understand the role
and therapeutic options of these antibodies in preeclampsia.

CONCLUSION
The current experimental data extends our knowledge of ATI-AA by displaying
that they play an important role in preeclampsia. AT1-AA may provide a link
between the various components of disease pathophysiology, in particular, the
immune, angiogenic and RAAS pathways.
However, there are many unanswered questions. Further studies are
required to isolate the molecular mechanisms responsible for this autoimmun-
ity and its relationship with preeclampsia and placental ischaemia.

DECLARATION OF INTEREST
The authors report no conflicts of interest. The authors alone are responsible
for the content and writing of this article.

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