CARDIOVASCULAR JOURNAL OF AFRICA • Vol 23, No 3, April 2012
AFRICA
157
1 mRNA levels, similar to the normotensive group, whereas in
the late-onset pre-eclamptic group, both values were raised. This
may indicate that the causes of hypertension in the chronic and
late-onset pre-eclamptic groups were not the same and that in the
latter group the raised serum sFlt-1 levels could be from other
sources.
Furthermore, in the early-onset pre-eclamptic group, the
serum sFlt-1 level was significantly greater than the normotensive
control group yet no significant differences in the placental
mRNA expression levels existed between these groups. This may
indicate either that there are other sources of sFlt-1 production in
early-onset PE other than the placenta, or that the placental tissue
sample may not have been a representative sample of placental
villi.
The serum sFlt-1 concentration in the late-onset pre-eclamptic
group was relatively less than in the early-onset pre-eclamptic
group. Our results support previous studies showing that
alterations in the serum sFlt-1 levels are more pronounced
in the early-onset pre-eclamptic group than in the late-onset
pre-eclamptic group.
34,35
Anumber of other studies have shown that
serum sFlt-1 levels in pre-eclamptic women are increased,
7,8,36-38
or unchanged,
39
when compared with normotensive patients.
These studies, along with ours, suggest that the placenta is
possibly a source of circulating sFlt-1.
38
In the normotensive group, although the sFlt-1 mRNA
expression levels appeared high, the VEGF mRNA expression
levels were equally high. Therefore, placental sFlt-1/VEGF
mRNA expression ratios were assessed to determine if there
was an imbalance between the levels of the angiogenic and anti-
angiogenic factors. In the normotensive group this ratio was
nearer to 1, indicating that the mRNA expression levels of sFlt-1
and VEGF were similar and therefore balanced.
On the other hand, the sFlt-1/VEGF mRNA expression ratios
in early-onset PE were very close to being significantly higher
than the normotensive group. The high serum sFlt-1 levels found
in the early- and late-onset pre-eclamptic groups corresponded
with the high placental sFlt-1/VEGF mRNA expression ratio,
suggesting that the imbalance in angiogenic and anti-angiogenic
factors begins at the placental level in early- and late-onset PE,
promoting an anti-angiogenic state.
SerumsFlt-1 concentrations have been extensively investigated
as a key protein that may be involved in the aetiology or as a
secondary phenomenon of PE.
40,41
Hypoxia is considered to be
the cause of the pathological excessive sFlt-1 production in
pre-eclamptic placentae.
1,42
It is believed that this soluble VEGF receptor 1 or sFlt-1
exerts its anti-angiogenic functions by binding to and inactivating
VEGF and PlGF. This is the basis of the antagonistic relationship
between sFlt-1 and VEGF. The authority of sFlt-1 lies in the
fact that it is capable of upsetting the delicate equilibrium, and
tipping the balance towards the anti-angiogenic state in PE.
This would, in turn, have a negative effect on the vasculature
since VEGF plays crucial roles in important processes such
as the control of angiogenesis. Notably, autocrine VEGF has a
trophic effect on the endothelium, distinct from its control of
angiogenesis. By inhibiting this effect, elevated sFlt-1 levels
may lead to systemic endothelial cell dysfunction, which is the
hallmark of the maternal stage of PE.
43,44
Another meaningful relationship has been demonstrated
between sFlt-1 and the RAS.
45
In addition to hypoxia causing
increased sFlt-1 production, recent studies have revealed
that AT1 autoantibody induces excess sFlt-1 production,
secretion and impaired angiogenesis in PE through undefined
mechanisms.
11,46
The AT1 autoantibody and hypoxia-induced
overproduction of sFlt-1 could activate a dangerous positive
feed-forward cycle wherein high sFlt-1 levels severely inhibit
angiogenesis and exacerbate the placental hypoxia observed in
PE, which subsequently causes an increase in placental sFlt-1
production.
40,47
Furthermore, recent studies have shown that AT1
receptor signalling regulates the genes encoding for proteins
associated with angiogenesis, such as sFlt-1.
47
In this study theAT1 receptor expression levels were relatively
lower in the normotensive, chronic hypertensive and early-onset
pre-eclamptic groups than in the late-onset pre-eclamptic group.
This can be expected in the normotensive group since in normal
pregnancies there is a reduced response to vasopressors.
48
However, AT1 receptor mRNA expression level in the late-
onset pre-eclamptic group was very close to being significantly
higher than in the early-onset pre-eclamptic group (
p
= 0.059),
suggesting that the RAS may be implicated in the pathogenesis
of PE in this group. This may also indicate that late-onset PE is a
different disease from early-onset PE and, therefore may actually
be a disease that has a closer association with the RAS than the
angiogenic/anti-angiogenic theory, as is the case in early-onset
PE.
The raised AT1 receptor mRNA expression level in late-onset
PE may be due to raised AT1 autoantibodies in this group.
40,49
Furthermore, we also found a significant correlation between
AT1 receptor mRNA levels and diastolic blood pressure in the
late-onset pre-eclampsia group (
p
< 0.05). Unfortunately, the
factors that activate the AT1 receptors, including angiotensin II
and the AT1 auto-antibodies were not quantified in this study.
Further studies using a larger sample size and measuring
AT1 receptor mRNA expressions, AT1 autoantibodies and
blood pressure in these two groups are necessary to prove this
hypothesis. Interestingly, a recent study showed that the increase
in AT1 autoantibodies might represent a better marker for late-
onset PE, whereas sFlt-1 is a better marker for early-onset PE.
50
To the best of our knowledge, this is the first time it has
been shown in black South African women that placental AT1
gene expression levels were relatively elevated in late-onset PE
compared with the early-onset pre-eclamptic, normotensive and
chronic hypertensive groups. In another study conducted on
black South African women, it was shown that the common RAS
polymorphisms could not be used to predict PE.
51
It has previously been shown that the blunted response to
angiotensin II during normal pregnancy is lost in pre-eclamptic
patients, who show a hypersensitivity to vasopressors.
48
This
may imply that there is no quantitative increase in vasopressors,
but rather an increase in sensitivity to the existing quantity of
vasoactive factors present in pre-eclamptic women. Our study
provides proof of this by showing elevated expression of the
AT1 receptors in late-onset pre-eclamptic patients compared to
the normotensive controls, chronic hypertensive and early-onset
pre-eclamptic groups, thereby accounting for the heightened
sensitivity to the powerful vasoconstrictor angiotensin II, which
is in accordance with previous studies.
52,53
Most studies on PE have been conducted on Caucasian
participants, and there is a paucity of information on other
ethnic groups. It is well documented that socio-demographic
