CARDIOVASCULAR JOURNAL OF AFRICA • Vol 23, No 3, April 2012
AFRICA
153
The role of angiogenic, anti-angiogenic and vasoactive
factors in pre-eclamptic African women: early- versus
late-onset pre-eclampsia
LUCINDA GOVENDER, IRENE MACKRAJ, PREM GATHIRAM, JACK MOODLEY
Abstract
The pathogenesis and aetiology of pre-eclampsia (PE) is
still unclear. We investigated the role of angiogenic, anti-
angiogenic and vasoactive factors in black South African
women with early- and late-onset PE. Serum soluble fms-like
tyrosine kinase 1 (sFlt-1), soluble vascular endothelial growth
factor (VEGF) and placental growth factor (PlGF) levels
were determined using the ELISA technique, and placental
mRNA expression levels of sFlt-1, VEGF, PlGF and AT1
receptors were determined using real-time PCR.
Serum sFlt-1 levels were significantly elevated and PlGF
significantly reduced in early-onset PE compared to the
normotensive group. Placental VEGF mRNA expression
levels were significantly reduced in the late-onset pre-
eclamptic group compared with the normotensives. The
placental mRNA expression of AT1 receptor in the late-onset
pre-eclamptic group was relatively raised compared to the
normotensives, suggesting hypersensitivity to pressor agents.
We believe that the excess of serum sFlt-1 and reduced
VEGF and PlGF levels favour an anti-angiogenic state and
endothelial dysfunction leading to PE, and that the aetiology
and pathogenesis of early- and late-onset PE differ.
Keywords:
pre-eclampsia, angiogenic factors, anti-angiogenic
factors, sFlt-1, VEGF, PlGF, placental AT1, VEGF, PlGF and
sFlt-1 mRNAs
Submitted 30/5/11, accepted 16/1/12
Cardiovasc J Afr
2012;
23
: 153–159
DOI: 10.5830/CVJA-2012-003
Pre-eclampsia (PE) is a pregnancy-specific syndrome that causes
substantial maternal, foetal and neonatal morbidity and mortality
worldwide.
1,2
It is characterised by new-onset hypertension and
significant proteinuria after 20 weeks of gestation, and the
remission of these signs following delivery.
Despite years of research, the exact aetiology of PE remains
unknown.
3
Much is, however, known about its underlying
pathophysiology.
4
It is recognised that PE is a multi-systemic
syndrome, affecting several organ systems and is posited
to occur in two
stages. Stage 1 comprises reduced placental
perfusion, which is postulated asthe root cause that leads to stage
2; the maternal syndrome.
5
The cause of the reduced perfusion
and the mechanism by which this is translated into the maternal
syndrome are still being investigated. The link between stages 1
and 2 may be the key to understanding and eventually treating PE.
It is believed that placental ischaemia during stage 1 may lead
to placental production of a soluble factor or factors that cause
maternal endothelial dysfunction.
1,6
One such anti-angiogenic
factor is soluble fms-like tyrosine kinase 1 (sFlt-1), a soluble
vascular endothelial growth factor (VEGF) receptor 1, which
has binding sites for soluble VEGF and placental growth factor
(PlGF). Therefore, excessive production of sFlt-1 in PE results in
a concomitant reduction of free, circulating angiogenic factors,
VEGF and PlGF.
7-9
When thematernal endotheliumis deprived of these angiogenic
factors (VEGF and PlGF) and in the presence of excess anti-
angiogenic factors such as sFlt-1, it becomes dysfunctional and
leads to the clinical syndrome of hypertension and proteinuria.
1,10
In addition to an imbalance between angiogenic and anti-
angiogenic factors, the renin–angiotensin system (RAS) has also
been implicated in the pathogenesis of PE.
11-13
Most studies on angiogenic/anti-angiogenic factors, however,
have been done in high-income countries. Furthermore, there
may be racial variations in both the incidence of PE and the
clinical features at presentation. For example, the incidence
of PE is much higher in South Africa and it has a much more
aggressive and rapid clinical course of presentation, leading
to significant mortality.
14
We therefore investigated the role of
serum and the placental mRNA expressions of angiogenic and
anti-angiogenic factors in African women with early- and late-
onset PE in a low- to middle-income setting.
Methods
Following institutional ethical permission, pregnant women who
gave written, informed consent were recruited from the labour
ward of a regional hospital in the KwaZulu-Natal province, South
Africa. Following enrolment, the participants were grouped
as follows: clinically healthy normotensive controls (
n
= 30);
chronic hypertensives (
n
= 9) (experimental control); early-onset
pre-eclamptics (
≤
27 weeks gestation) (
n
= 10) and late-onset
pre-eclamptics (
≥
28 weeks gestation) (
n
= 9).
Definitions: pre-eclampsia was defined as new-onset
hypertension (blood pressure 140/90 mmHg) and proteinuria
(
≥
2+ on testape) after the 20th week of pregnancy. Chronic
hypertensionwas defined aswomenwith a history of hypertension
Department of Physiology and Physiological Chemistry,
University of KwaZulu-Natal, Durban, South Africa
LUCINDA GOVENDER, MMedSci
IRENE MACKRAJ, PhD,
Department of Family Medicine, Nelson R Mandela School
of Medicine, University of KwaZulu-Natal, Durban,
South Africa
PREM GATHIRAM, PhD
Department of Obstetrics and Gynaecology and Women’s
Health and HIV Research Group, Nelson R Mandela School
of Medicine, University of KwaZulu-Natal, Durban,
South Africa
JACK MOODLEY, MD,
