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PATHOPHYSIOLOGY

Primary cause unknown (genetic/ immunological

Initial phase: Vascular pathology

Failure of second wave of trophoblast invasion

Decrease blood flow in spiral artery

Decrease placental blood flow

Placental bed ischemia

Stimulation of macrophage system

Oxygen free radicals

 Endothelial damage/ dysfunction

Unknown primary cause (immune or genetic)

Three levels characterize the pathology of pregnancy-induced hypertension. Although

the exact pathology is unknown, trophoblast presence is at least linked to it. The

mother's adaptation to the compromised endovascular trophoblast invasion and acute

atherosis is the secondary pathology of pregnancy-induced hypertension. The two main

symptoms of pregnancy-induced hypertension—hypertension and proteinuria—are

examples of secondary pathology. Pregnancy-induced hypertension's peripheral

disruptions have the potential to worsen to the point where they cause new, tertiary

pathology, or the third level. The HELLP (hemolysis, elevated liver enzymes, low

platelets) syndrome, cerebral hemorrhage, eclampsia, and renal failure are the most

notable manifestations of tertiary pathology.

It is currently unknown what causes pregnancy-induced hypertension in the first place.

Genetic influences play a role. It is more likely that a number of genetic variables are

linked to maternal susceptibility than that there is a single major gene that causes

pregnancy-induced hypertension. It has been proposed that immunological

maladaptation contributes to preeclampsia. Increases in cytokines and free radicals

may result from the presumed misalliance of fetal trophoblast with maternal tissue in the

uteroplacental vascular bed.

The first stage is vascular pathology.

Major systemic hemodynamic adaptations in normal pregnancies include increases in

cardiac output, expansion of plasma volume, and decrease in total vascular resistance.

Reduced vascular tone is seen in the systemic mother arteries, which lowers peripheral

vascular resistance. Systemic maternal arteries from women with pregnancy-induced

hypertension exhibit endothelial dysfunction, which is distinguished from normal

pregnant women by endothelial injury, diminished dilatory responses, and an imbalance

in the bioavailability of substances derived from the endothelium that produce

vasoactive substances. We will also consider the role that vascular smooth muscle-

specific pathways play in systemic maternal vascular dysfunction. The present review

will not delve into the role of circulating angiogenic factors and circulating inflammatory

factors as mediators of endothelial activation in pregnancy-induced hypertension, as

this has been thoroughly discussed in prior reviews.

Failure of second wave of trophoblast invasion

Failure of trophoblast invasion and spiral artery transformation has been documented in

pregnancy induced hypertension (PIH), one of the leading causes of maternal death. In

this syndrome reduced uteroplacental perfusion is associated with widespread

endothelial dysfunction and fetal growth restriction (FGR) leading to significant maternal

and perinatal morbidity. Similar spiral artery abnormalities have been reported in the

placental bed of women with FGR and spontaneous abortion in the absence of maternal

hypertension. Thus, failure of the spiral arteries to undergo physiological transformation

may lead to a spectrum of pregnancy failures. Despite the importance of trophoblast

invasion and vascular remodeling, these processes are still not well understood.

However, they are thought to include changes in expression of cell adhesion molecules,

matrix metalloproteinases and their tissue inhibitors, and growth factors and their

receptors.

Decrease blood flow in spiral artery.

The main pathological feature of early-onset is incomplete transformation of the spiral

arteries, resulting in hypoperfusion of the placenta and reduced nutrient supply to the

fetus. This results in signs of fetal growth restriction. On the other hand, in late-onset

type, the spiral arteries, if at all, are slightly altered in diameter and there are no signs.

This is because early-onset pre-eclampsia is related to placental hypoperfusion, while in

the late-onset type there is either no change or a shallow modification of the spiral

arteries, leading in some cases to hyper perfusion of the placenta.

Decrease placental blood flow

In pregnancy induced hypertension, 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 remodeling and acute artherosis. In vivo techniques (magnetic resonance

imaging and Doppler low-flow measurements) have confirmed this in early- but not late-

onset PE. 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. 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. 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.

Placental bed ischemia

In a subset of pregnant women these physiological modifications do not occur. The

terminal portions of the vessels do not dilate normally, smooth muscle remains in the

vessel wall and the modification of the vessels does not extend beyond the decidual

layer resulting in the maintenance of the “functional sphincter”. These findings are very

similar in pregnancies with preeclampsia, intrauterine growth restriction, recurrent

pregnancy loss and in one third of cases of preterm birth9 and likely in a percentage of

“normal pregnancies.

The alterations of the placental blood supply associated with placental ischemia lead to

local and systemic pathophysiological changes. The changes in the spiral arteries and
in uterine vessels proximate to these vessels reduce to some extent the delivery of

nutrients and oxygen to the intervillous space. As described, this is not nearly as striking

as has been posited in the past. It appears that the increased velocity of blood passing

through the intervillous space is more pertinent to the reduced oxygen and nutrient

delivery. Because of reduced time in the intervillous space there is reduced extraction of

gasses and nutrients. This leads to the interesting possibility that because of reduced

extraction, the blood in the intervillous space is hyperoxic exposing the fetal surface of

the placenta to increased oxygen concentration while at the same time reduced

extraction renders the majority of the placenta hypoxic. It is proposed that this

combination and the residual responsiveness of the incompletely remodeled spiral

arteries results in the generation of oxidative stress.

Stimulation of macrophage system

Macrophages play a key role in the maintenance of tissue homeostasis, regulation of

inflammatory processes and tissue repair. In accordance with modern concepts, tissue

macrophages in mammalian ontogenesis develop from three sources that correspond to

three generations of hematopoietic progenitor cells.

The first generation of hematopoietic cells is specified within the wall of the yolk sac. It

is important to note that these hematopoietic cells have a different origin than progenitor

cells developing from hematopoietic islets in the endothelium of yolk sac capillaries.

The second generation, erythro-myeloid progenitor cells, is formed from the

hematogenic endothelium of the yolk sac capillaries. These cells subsequently colonize
the embryo’s liver. By the profile of molecular markers, macrophages derived from these

progenitors are very similar to macrophages derived from the first generation of

progenitors; however, their maturation involves the stage of monocytes.

The third generation of hematopoietic progenitors develops from the hematogenic

endothelium of the aorta–gonad–mesonephros zone; these cells subsequently migrate

to the liver and red bone marrow. Macrophages derived from this generation colonize

almost all organs of the embryo except the central nervous system.

Thus, macrophage populations of most organs in the prenatal period consist of

hematopoietic cells descending from the second and third generations. In most of them,

the proportion of macrophages descending from erythro-myeloid progenitor cells of the

yolk sac is being gradually decreased, and accordingly the proportion of macrophages

descending from hematopoietic cells of the third generation is increased.

Oxygen free radicals

Oxygen free radical production is commonly increased in women with pregnancy

induced hypertension. Although a physiological balance between lipid peroxides and

antioxidative processes is maintained during a normal pregnancy, an imbalance may

occur, thereby increasing the oxidative stress in preeclamptic women. In the present

study, we found that d-ROM concentrations in the blood were significantly higher in the

severely preeclamptic group, but not in the mildly preeclamptic group, compared with

the control group. In contrast, BAP concentrations did not change significantly across all

three groups. These results indicate that the balance between oxygen free radicals and
antioxidative processes is maintained in mildly preeclamptic women, but not in severely

preeclamptic women. The results also indicate that this imbalance is dependent on

increased oxygen free radical production and not on decreased antioxidative processes.

Endothelial damage/ dysfunction

The maternal vascular endothelium appears to be an important target of factors

triggered during pregnancy induced hypertension. Both endothelium-derived relaxing

and contractile factors play an important role in the regulation of arterial compliance,

vascular resistance, and blood pressure. When abnormalities in the production or action

of these factors occur, the vasculature is predisposed to vasoconstriction, leukocyte

adherence, oxidative stress, and vascular inflammation. Once immune cells adhere to

the activated vascular endothelium a series of cellular interactions occur inducing

junction widening between cells and allowing immune cell infiltration into the vascular

wall thereby invading local tissues. As a result, the endothelium becomes leaky allowing

for extravasation of fluid, recognized clinically as edema. Therefore, markers of

endothelial dysfunction may serve as predictors of the syndrome in women that develop

pregnancy induced hypertension since many are often elevated weeks prior to

observance of clinical manifestations.