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

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

AFRICA

and child, and furthermore the pathogenic processes could

be multifactorial. In any event, it is generally felt that lack of

adequate placental development is the root cause of early-onset

PE because the only known treatment of the disorder is delivery

of the foetus and placenta. It is, however, essential to understand

the features of placental development in normal pregnancies in

order to understand the pathophysiology of PE.

Role of the placenta in normal pregnancies

Placentation and trophoblast invasion of the maternal tissue

involves two processes, firstly vascularisation to establish a

foeto-placental vascular network, and secondly, invasion of the

maternal spiral arteries by the cytotrophoblasts or endovascular

trophoblasts (EVTs).

At the time of implantation, trophoblastic

cells differentiate into cytotrophoblasts and syncytiotrophoblasts.

The cytotrophoblasts form the extravillous trophoblasts (EVT),

which invade the decidual and junctional zone myometrial

segments, the inner third of the myometrium and the spiral

arteries. The EVTs induce remodelling of the latter, perhaps by

causing loss of the elastic lamina, most of the smooth muscle

cells, and temporarily replacing the endothelial cells,

thus

transforming a high-resistance, low-flow vascular system into

a low-resistance, high-flow type, essential for normal foetal

growth.

13,14

Therefore, the cytotrophoblasts, epithelial in nature, replace

the endothelial cells and in the process, the epithelial-like

receptors are replaced with maternal adhesion molecules

such as vascular endothelial (VE) cadherin vascular adhesion

molecule-1, platelet-endothelial molecule-1, and

3 integrin.

This perhaps accounts for the prevention of foetal rejection. The

trophoblasts therefore take on the phenotype of endothelial cells

and are in direct contact with maternal blood, but the maternal

and foetal blood do not mix.

The syncytiotrophoblasts are multinucleated, line the

chorionic villi, and act as an interface between maternal and

foetal blood. However, according to Brosens

et al

. (2011),

trophoblast invasion of the spiral arteries is preceded by oedema

of the vessel wall, disintegration of the elastic fibres and changes

in the smooth muscle layer, leading to a loss of myofibrils.

Hence

it is not the generally believed concept that the trophoblastic cells

themselves cause disintegration of the elastic fibres and loss of

myofibrils. In addition, development of the foetus initially occurs

under low oxygen tension and placental perfusion is only from

the intervillous space, and unplugging of the maternal spiral

arteries occurs at about the 12th gestational week.

The migration of trophoblasts into the spiral arteries is

influenced by a number of factors such as cytokines, growth

factors, oxygen tension, and the local cellular environment,

for example immune cells such as macrophages and decidual/

uterine natural killer (dNK) cells.

The dNK cells are thought to

play an important role in regulating placentation but the exact

mechanism of action is still unclear.

Systemic inflammatory response in normal

pregnancies

The foetal trophoblast is regarded as an allo-antigen and the

mother reacts to this and mounts a sterile, low-grade systemic

inflammatory response.

4,19

It is thought that syncytiotrophoblast

microparticles (STMBs) detected in the maternal circulation

could be the cause.

However, it is known that utero-foetal

perfusion only begins towards the end of the first trimester,

while increased levels of STMBs in the maternal circulation

are detected during the second and third trimesters.

The

initial inflammatory response during the first trimester could

be due to an interaction between the decidual immune cells

and trophoblast cells, and that a secondary inflammatory

response during the second and third trimester could be due to

syncytiotrophoblast microparticles released into the mother’s

vascular system.

21,22

Placental blood flow in pre-eclampsia and its

consequences

In PE, it has almost been established that there is reduced blood

flow to the placenta, especially in the early-onset type, because

of defective spiral artery remodelling and acute artherosis.

23,24

In vivo

techniques (magnetic resonance imaging and Doppler

low-flow measurements) have confirmed this in early- but not

late-onset PE.

In PE the defects in spiral artery remodelling are restricted

to the distal segments of the spiral arteries, that is the proximal

decidua and the junctional zone (JZ) myometrial segments, and

hence the myometrial spiral arteries still have much of their

smooth muscle cells and elastic lamina, with absent or partial

transformation of the arteries in the JZ myometrial segment.

4,15

The exact mechanism for this is not known but various factors,

such as abnormal genetic variations, biology of the trophoblasts

or defective trophoblast differentiation acting together with

extrinsic factors, such as maternal constitutional factors, action

of macrophage defense mechanisms, impaired action of dNK

cells and maternal endothelial cells have been advanced.

18,23,25

Recently, it has been proposed that proteolytic activity of the

different populations of the EVTs could be involved in invasion

of the decidua and spiral arteries.

Studies conducted in our laboratories showed that a PE-like

syndrome canbe produced in a ratmodel by reducing the placental

blood flow through the administration of nitro-L-arginine

methyl ester (L-NAME).

27,28

In addition, co-administration

of sildenafil citrate, which blocks the action of L-NAME,

prevented the PE-like syndrome. Furthermore, we have shown

that once the administration of L-NAME is discontinued, the

pathophysiology of PE continues until birth of the pups, and

thereafter the high blood pressure and proteinuria return to

almost normal levels.

The question then arises as to what the effects of the

reduced placental blood flow or hypoperfusion on the maternal

syndrome, namely hypertension, proteinuria and oedema, are. Is

it the reduced blood flow

per se

that triggers events leading to

the maternal syndrome, or is it some other factor/s associated

with ischaemia?

It is believed that reduced placental blood flow could result

in hypoxia of the placenta, which has been suggested as the

ultimate cause of PE.

19,30

However, no

in vivo

measurements of

oxygen tension in the intervillous space have been made to claim

that hypoxia does occur.

Nevertheless, it is believed that that

reduced blood flow or chronic hypoxia on their own are not

the direct cause of the placental lesions seen in PE but could

be a contributing factor. It has therefore been assumed that