CARDIOVASCULAR JOURNAL OF AFRICA • Vol 24, No 5, June 2013
178
AFRICA
is highly expressed in syncytiotrophoblasts and endothelial
cells.
29,33
It is identified as a pro-angiogenic factor that regulates
vascular remodelling and homeostasis via the endothelial nitric
oxide synthase pathway.
29,32-34
In contrast, sEng prevents the
signalling pathway of TGF-
β
1
and the endothelial stimulation
of TGF-
β
1
-mediated nitric oxide synthase pathway, thereby
obstructing endothelial and capillary development.
31,35
Consequently, the anti-angiogenic effects of sEng evident in
pre-eclampsia occur via its interaction with TGF-
β
1
, resulting
in the inhibition of the endothelial attachment of TGF-
β
1
and
the subsequent loss of the endothelial pro-angiogenic and
vasodilatory effects of TGF-
β
1
.
22,31,34,35
Therefore the clinical
significance of elevated levels of sFlt1 and sEng and their role
as powerful anti-angiogenic factors through their interaction with
the circulating levels of VEGF, PlGF and TGF-
β
1
, respectively, is
well established.
Our study confirmed previous reports of elevated serum levels
of sFlt1 and sEng in pre-eclamptic compared with normotensive
groups.
10,27,36
In addition, we showed a significant difference
for sFlt1, sEng and PlGF between all groups. Furthermore,
sFlt1 and sEng were higher in the pre-eclamptic (HIV negative
and positive) compared with normotensive pregnancies (HIV
negative and positive).
In our study, the HIV-negative normotensive pregnant women
had higher levels of PlGF compared with both pre-eclamptic
groups, confirming previous reports.
21,27,37
PlGF was reduced in
the HIV-positive normotensive versus both the HIV-negative and
HIV-positive pre-eclamptic groups. Pre-eclampsia is associated
with decreased levels of PlGF, with the concurrent increase
of sFlt1. This trend was observed in our study among the
HIV-negative normotensive versus the pre-eclamptic groups.
Unexpectedly, this trend was reversed in the HIV-positive
normotensive group. It is therefore possible to assume that the
immune insufficiency stimulated by HIV infection reduced
a predisposition to immune hyper-reactivity, forestalling
the development of pre-eclampsia. Moreover, there was a
significantly higher difference between the HIV-negative and the
HIV-positive normotensive groups.
The sFlt1/PlGF ratio has diagnostic predictor test value
for pre-eclampsia.
38,39
It is therefore evident that the clinical
significance of the sFlt1/PlGF ratio, which represents the anti-
angiogenic role in pre-eclampsia, characterises the stability
between sFlt1 and PlGF. Our results showed a lower sFlt1 and
sFlt1/PlGF ratio in the HIV-positive pre-eclamptic compared
with the HIV-negative pre-eclamptic groups, indicative of an
apparent trend towards a diagnostic value. The imbalance that
occurs in pre-eclampsia may be attributed to the immunological
nature of the disease, however this requires further investigation.
Unlike sFlt1 in the HIV-positive pre-eclamptics, sEng
varied compared with the HIV-negative pre-eclamptic groups.
Furthermore, when combined as an anti-angiogenic ratio (sEng/
TGF-
β
1
), a significantly lower difference was evident between
the control and pre-eclamptic groups. The HIV-negative and
HIV-positive pre-eclamptic pregnant females showed higher
sEng/TGF-
β
1
ratios compared with both normotensive groups.
The HIV-positive pre-eclamptics showed a higher ratio
compared with the HIV-negative pre-eclamptic groups, while the
average ratios of the HIV-positive normotensives were lower than
the HIV-negative normotensive pregnant women. These results,
albeit in term pregnancies, suggest that these ratios may have a
clinical significance during early pregnancy as a predictor test
for the development of pre-eclampsia.
An elevation of plasma and platelet-depleted plasma levels
of TGF-
β
1
in pre-eclampsia compared with normotensive
pregnancy has previously been reported.
40
Our study, however,
demonstrated no significant differences in serum TGF-
β
1
levels,
with a concomitant significance of sEng/TGF-
β
1
ratio for the
HIV-positive pre-eclamptics versus HIV-positive normotensives,
and the HIV-negative pre-eclamptics versus HIV-positive
normotensives.
Our results were similar to, albeit higher than, that observed
by Huber
et al.
(2002), showing no significant difference in
TGF-
β
1
expression between the pre-eclamptic and normotensive
groups.
41
Noteworthy, the analyses of sEng/TGF-
β
1
ratio in
our study implicated a role for TGF-
β
1
in the pathogenesis
of pre-eclampsia. However, a limitation to our study was
the relatively small sample size, and this requires further
investigation.
Conclusion
Our study demonstrated elevations in both sFlt1 and sEng levels
in pre-eclamptic compared with normotensive pregnancies,
irrespective of the HIV status. Quantification of serum
pro-angiogenic/anti-angiogenic factors in HIV-associated
pre-eclampsia is novel.
This study was supported by the Durban University of Technology and the
National Research Foundation (grant number 69086), South Africa. We
thank Mrs T Esterhuizen, Mr S van der Linde and Dr S Naidoo for advice on
statistical and ELISA analyses, respectively.
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