Cardiovascular Journal of Africa: Vol 27 No 2 (March/April 2016)

CARDIOVASCULAR JOURNAL OF AFRICA • Volume 27, No 2, March/April 2016

AFRICA

the lesions could rather be due to an ischaemia–reperfusion

or hypoxia–reoxygenation (HR) type of injury caused by free

radicals such as reactive oxygen species (ROS).

Furthermore, it has been speculated that an intermittent

type of blood flow occurs in the intervillous space, which could

be responsible for the HR type of injury.

To support this,

Yung

et al

. in 2014

showed that high levels of activation of

unfolded protein-response pathways due to HR damage to the

endoplasmic reticulum occurred in placental samples taken

from early- but not late-onset PE. Accumulation of aggregates

of unfolded protein response (UPR) or misfolded proteins has

been observed in PE placentas and it is believed that these may

contribute to the pathophysiology of the disorder.

However, no

measurements have been made to show that blood flow to the

intervillous space is indeed intermittent. We believe that it is the

pulsatile nature of blood flow from the spiral arteries that could

be responsible for the HR type of injury.

The defective spiral arteries lead to further deterioration in

placental perfusion, ischaemia and worsening of the already

hypoxic condition seen in normal pregnancies.

The HR damage

to the placenta, however, results in increased stress of the

syncytiotrophoblasts, causing necrosis, apoptosis and release

of excess placental debris (STMBs and vesicles), compared to a

normal pregnancy, into the maternal circulation.

In addition,

soluble endoglin (sEng) is the extracelluar component of Eng,

which is highly expressed in the syncytiotrophoblasts, and

shedding of STMBs causes either mechanical disruption or

proteolytic cleavage of sEng, and excess amounts of it are present

in PE. The details of this are discussed later in this review.

It is therefore believed that placental ischaemia–reperfusion

injury is central to the development of PE. In addition to

STMBs, pro-inflammatory cytokines, responsible for endothelial

dysfunction and increased inflammatory responses, lead to

the clinical signs of PE, such as hypertension, proteinuria and

thrombotic micro-angiopathy, presenting as haemolysis, elevated

liver enzymes and low platelet count (HELLP) syndrome,

pulmonary or cerebral oedema and seizures.

35,36

However, there

is no clear evidence that this really occurs and it has not

been conclusively proven that STMB vesicles, and micro- and

nanoparticle levels are significantly raised in PE compared to

normal pregnancies, and that these substances give rise to the

inflammatory disorder seen in PE.

Pro-angiogenic and anti-angiogenic factors in

pre-eclampsia

Pro-angiogenic factors, VEGF, PlGF and TGF-

Vascular endothelial growth factor (VEGF) and platelet growth

factor (PlGF) play a key role in placental angiogenesis and are

believed to be secreted by trophoblast cells. VEGF is thought to

be essential for integrity of the maternal endothelial cells.

Both

elevated and reduced levels of VEGF in the maternal circulation

have been reported in PE.

These conflicting results could be due

to the methodologies used. Elevated levels could perhaps be due

to the use of commercial kits that measure both the bound and

the soluble forms of VEGF in the maternal circulation.

A longitudinal study showed that serum PlGF concentrations

increased from 15–19 pg/ml through to 21–25 gestational weeks,

and peaked at 27–30 weeks in uncomplicated pregnancies, in

women with small-for-gestational-age (SGA) neonates and

PE without SGA neonates, and thereafter the levels declined

towards 35–36 gestational weeks.

However, in PE complicated

by SGA, the peak occurred at 21–25 gestational weeks, but at all

times the levels were lower than in women with PE only.

The transforming growth factor-

(TGF-

) family,

especially TGF-

and TGF-

have also been implicated in

pre-eclampsia,

40,41

but their exact mechanism of action is not

known except to say that they are expressed in the pre-eclamptic

placenta and reduce trophoblast proliferation, migration and

invasion.

Anti-angionenic factors sFlt-1 and sEng

The anti-angiogenic factors are VEGF receptors (VEGFR1 and

VEGFR2) and Eng. VEGFR1 is also known as fms-like tyrosine

kinase-1 (Flt-1), which is membrane bound, while VEGFR2 is

known as kinase insert domain receptor (KDR).

42,43

It is known

that sFlt-1, a spice variant of Flt-1, is the free form found in the

circulation.

Soluble Eng has anti-angiogenic effects, and as it

has binding sites for TGF-

1 and

it is thought to play a

role in PE.

Venkatesha

et al

. found that Eng mRNA expression was

significantly up-regulated in placental tissue (obtained at

delivery), particularly in syncytiotrophoblasts in PE at 25 and 40

gestational weeks compared to age-matched control pregnancies.

These researchers also found that this was accompanied by a

significant rise in sera levels (obtained before delivery) of sEng in

PE women compared to control pregnancies, and concluded that

both sEng and sFlt-1 could be blocking the actions of TGF-

and VEGF, respectively. However, no significant differences in

serum TGF-

1 levels were detected between normal-pregnancy

and PE women.

Venkatesha

et al

. further showed that administration of

sEng to pregnant rats significantly increased the mean arterial

pressure at 17–18 days of pregnancy but it had mild to modest

effects on proteinuria. However, co-administration of sFlt-1

caused high levels of proteinuria, hypertension and evidence of

the HELLP syndrome.

Imbalance in angiogenic and anti-angiogenic

state in PE

There is increasing evidence that suggests an imbalance between

pro-angiogenic and anti-angiogenic factors are responsible

for the pathophysiological effects seen in PE,

46,47

and these

appear before clinical signs are apparent.

However, it is not

exactly known why some women develop PE while others with

similar features, such as placental ischaemia and endothelial

dysfunction, give birth only to SGA neonates without classical

clinical signs of the disorder.

Serum samples taken at the time of delivery have shown

significantly increased sFlt-1 and decreased VEGF and PLGF

concentrations in PE, compared to normotensive controls.

In vitro

studies showed that serum from PE inhibited tube

formation in human umbilical vein endothelial cell (HUVEC)

lines compared to that from controls, and administration

of adenovirus expressing sFlt-1 to pregnant rats caused

hypertension, albuminuria and glomerular endotheliosis, similar

to that observed in PE.