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CARDIOVASCULAR JOURNAL OF AFRICA • Volume 27, No 2, March/April 2016
AFRICA
75
Placental hypoxia and perhaps oxidative stress, which occurs
in PE, is also known to upregulate the gene expression and
formation of Eng in placental tissue, perhaps via TGF-
β
3
.
67,68
The
action of Eng and its receptor sEng have already been discussed.
Perhaps in a similar manner, there is over-expression of genes
responsible for the formation of sFlt-1, PlGF and VEGF in PE
placentas.
65,68
However, it has to be noted that for ethical reasons,
it is difficult to study gene expression in placentas prior to actual
clinical diagnosis of PE.
The RAAS and angiotensin II AT-1 receptor
auto-antibodies
In a recent review article Verdonk
et al
. presented a detailed
account of the involvement of RAAS and Ang II AT-1
receptor auto-antibodies (AT-1AA) in the pathophysiology
of pre-eclampsia.
10
Readers are advised to refer to Verdonk
et al
.
10
for details. They stated that in normal pregnancies,
particularly in the early stages of gestation, there is an increase
in maternal blood volume and a decrease in total resistance, and
to counteract a fall in blood pressure, the RAAS is activated,
resulting in sodium and water retention. However, in PE in
contrast to normal pregnancy, the intravascular blood volume
and cardiac output are reduced, while the total peripheral
resistance is increased, and most components of the RAAS are
downregulated.
10
These findings led them to conclude that in pre-eclampsia,
the suppression of most components of the RAAS could lead
to increased response to Ang II and AT-1AA. They reported
that the exact role of the RAAS and AT-1AA systems in PE
remains unanswered, suffice to state that the sensitivity of Ang II
receptors to Ang II is increased, and angiotensinogen synthesis
is stimulated by high circulatory oestrogen levels in the first 10
weeks of pregnancy.
10
High-molecular weight angiotensinogen levels were found to
be about 25% higher than total angiotensinogen levels in PE,
compared to 16% in normal pregnancy.
69
However, it has been
found that plasma renin activity, Ang II and aldosterone levels
were decreased.
70
At present, evidence of the exact role of the
RAAS in PE is therefore lacking.
Circulating auto-antibodies to AT-1AA have been shown to
increase after 20 weeks of gestation.
71
Others have shown that
AT-1AA was more predictive in late-onset than in early-onset
PE.
72
It is possible that Ang II, by activating the AT-1 receptors
on human trophoblasts, could play a role in shallow trophoblast
invasion of the spiral arteries through secretion of plasminogen
activator inhibitor-1 (PAI-1). Similar findings for AT-1AA were
noticed in
in vitro
studies using human mesangial cells, where it
caused increased secretion of PAI-1 and IL-6, compared to IgG
from normotensive patients.
73
It was further speculated that the
latter actions of AT-1AA could account for the renal damage
seen in PE patients.
73
Xia and Kellems have presented a detailed review on the
pathophysiological role of AT-1AA.
74
They have shown that that
these auto-antibodies play a critical role in PE, and blockade
of AT-1 receptors in animal models reversed the signs and
symptoms of PE by reducing the circulatory levels of sFlt-1 and
IL-6.
74
However, it remains to be shown conclusively that in human
patients, AT-1AA plays an important role in the pathophysiology
of PE, since most of the experiments were conducted in animal
models, which may not represent what happens in PE. In
addition, it has not been conclusively shown that in every
pre-eclamptic woman, the levels of AT-1AA are raised.
Hydrogen sulphide
Hydrogen sulfide (H
2
S) is a gaseous signalling molecule in
humans and animals. It is produced in endothelial cells.
75
It has
vaso-relaxant properties and is involved in uterine contractility.
76,77
Endogenously produced H
2
S also has angiogenic
75
and anti-
inflammatory properties.
75,78
In the latter case, H
2
S acts at the
endothelial–leukocyte interface.
78
Chronic administration of H
2
S
was found to have hypotensive effects in a rat model and reduced
infarct in ischaemic–reperfusion injury in experimental rats.
79
The production of H
2
S requires one of two enzymes:
cystathionine
γ
-lyase (CSE) or cystathionine
β
-synthase (CBS).
80
Both these enzymes are localised in foetal endothelial cells of
both the stem and chorionic villi, and the Hofbauer cells express
CBS mRNA.
80
In early-onset but not late-onset PE, CBS mRNA expression
was down-regulated.
80
A recent study showed that mRNA
expression of CSE was reduced in pre-eclamptic placental tissue
and in women with SGA neonates, compared with normal
pregnancy.
81
The reduction in CSE expression was accompanied
by reduction in the concentration of H
2
S in the maternal
circulation.
81
In addition, it was found that trophoblasts and
mesenchymal cells in the core of the chorionic villi were the sites
for expression of CSE.
81
Inhibition of CSE by DL-propargylglycine (PAG) in pregnant
mice resulted in hypertension and elevation in sFlt-1 and sEng
levels in the circulation, and also caused placental abnormalities,
while administration of GYY4137, which inhibits the action
of PAG, reduced the levels of circulating sFlt-1 and sEng and
restored foetal growth.
81
This illustrates that H
2
S is required for
placental development.
Furthermore, it was also shown in
in vitro
studies that
dysregulation of the CSE/H
2
S pathway affected spiral artery
remodelling and placental development.
81
In addition, it was
found that inhibition of CSE with PAG in placental explants
taken from first-trimester pregnancies reduced PlGF production.
Wang
et al.
are of the view that their findings imply that
endogenous H
2
S is required for placental development and foetal
and maternal well-being.
81
These findings perhaps show that H
2
S
plays a role in the pathogenesis and pathophysiology of PE.
However, it is felt that plasma H
2
S levels were overestimated in
some of the above studies and may not reflect the true values.
82
Nulliparity has been suggested as a risk factor for PE.
83
The
risk of pre-eclampsia was 26% in nulliparous patients versus
17% in parous [RR and 95% CI: 1.5 (1.3–1.8)] subjects. The risk
of PE is also increased with a history of abortion and changed
paternity. There seems to be a genetic component. Both mother
and foetus contribute to the risk of PE, the contribution of
the foetus being affected by paternal genes. An immune-based
pathology is also proposed, whereby prolonged exposure to
foetal antigens protects against PE in a subsequent pregnancy
with the same father.
84,85
Finally, a reason why PE is more
common in nulliparous than multiparous women could be that
in the latter, the uterine and spiral arteries develop a larger bore,
which is easier for trophoblastic invasion.
83