The vascular endothelium in normal pregnancy and pre-eclampsia
←
→
Page content transcription
If your browser does not render page correctly, please read the page content below
Reviews of Reproduction (1996) 1, 107–116
The vascular endothelium in normal pregnancy and pre-eclampsia
Fiona Lyall and Ian A. Greer
Department of Obstetrics and Gynaecology, University of Glasgow, Glasgow Royal Infirmary,
10 Alexandra Parade, Glasgow G31 2ER, UK
Hypertensive disorders of pregnancy affect up to 15% of pregnancies and the most severe
form, pre-eclampsia, is the leading cause of maternal death in the UK today. Pre-eclampsia is
a multisystem disorder affecting virtually every organ and system in the body, with hyper-
tension and proteinuria, the traditional diagnostic features, representing two facets of a com-
plex pathophysiological process. The common pathological feature of the disease, whether in
the decidual vessels of the placental bed, renal microvasculature, liver, heart or cerebral circu-
lation, is vascular endothelial damage and dysfunction. Before new ways of preventing or
ameliorating hypertensive disorders of pregnancy can be found, we must first understand the
pathophysiological mechanisms underlying the clinical problem. This review summarizes the
evidence that endothelial dysfunction plays a key role in hypertensive disorders of pregnancy
and will focus on the most severe form, pre-eclampsia.
Three types of hypertension can occur in pregnancy. First, and nitric oxide (NO) which can inhibit the activation of plate-
pregnancy may occur in patients with pre-existing hyperten- lets and neutrophils and substances, such as tissue plasmin-
sive disease. Second and rarely, hypertension may result from ogen activator (tPA), that prevent or limit coagulation and
a coincidental development of a new medical cause occurring vascular damage. The glycosaminoglycans of the endothelial
in pregnancy, such as phaeochromocytoma. Third, there are cell plasma membrane are rich in heparin sulfate and so bind
women who are normotensive before pregnancy and in early antithrombin, increasing its affinity for thrombin. This allows
pregnancy but who develop hypertension during pregnancy rapid clearing of thrombin. The endothelium also controls co-
that remits within a few months of delivery; these women have agulation by surface expression of thrombomodulin which
pregnancy-induced hypertension. Pre-eclampsia is a severe form binds to thrombin, simultaneously lowering its affinity for
of pregnancy-induced hypertension and occurs at frequencies of fibrinogen and increasing its ability to activate protein C.
between 1% and 5%. It is characterized by high blood pressure Protein C is an anticoagulant that inactivates factor Va, factor
in late pregnancy (90 mmHg or a rise of 25 mmHg) and pro- VIII and plasminogen activator inhibitor. Endothelial cells also
teinuria (0.3 g per 24 h) with a wide range of pathophysiologi- contribute to the action of protein C by secreting its co-factor,
cal organ and system disturbances. It can lead to the occurrence protein S. Endothelial cells are a source of adenine nucleotides,
of epileptic-like grand mal convulsions (eclampsia) in about which under certain circumstances cause vasodilatation.
0.1% of pregnancies. Cerebral vascular accident is the most Conversely, the endothelium can render itself thrombogenic
common cause of death. The disease has no known cause by secreting von Willebrand’s factor, which stabilizes factor VIII
and can only be cured by delivery of the fetus and placenta. and acts as a cofactor for the adhesion of platelets. It also secretes
Pre-eclampsia remains the major cause of maternal death in the platelet-activating factor, an important mediator of platelet/
UK to-day; it is also a major contributor to maternal and peri- fibrin formation. These latter factors would normally promote
natal morbidity and perinatal mortality. Furthermore, recent local coagulation and repair at the site of injury. The endo-
epidemiological evidence suggests that intrauterine growth re- thelium can contribute directly to thrombosis by the release of
tardation (IUGR), the risk of which is increased in pre-eclampsia, plasminogen activator inhibitor-1 (PAI-1), which counteracts
may be linked to the development of cardiovascular disease in the fibrinolytic effects of tissue type plasminogen activator
adult life. Despite increasing knowledge of its pathophysiologi- (t-PA), preventing or limiting coagulation and vascular
cal processes, the aetiology of this condition remains obscure. damage, and thus promoting blood coagulation (Fig. 1). These
The common pathological feature of the disease, whether in the events have been reviewed in detail by Bloom et al. (1994).
placental bed, renal microvasculature or cerebral circulation, is The endothelium also influences vascular tone by releasing
vascular endothelial damage and dysfunction. vasodilator substances such as prostacyclin and NO, and vaso-
General reviews on the pathophysiology and aetiology of constrictors such as endothelin. It is also intimately linked to
pregnancy-induced hypertension have been published else- the actions of the vasodilator atrial natriuretic peptide (ANP)
where (Greer, 1992; Lyall and Greer, 1994, 1995a). and to the renin–angiotensin system. Endothelial cells also ex-
press ectopeptidases that can convert angiotensin I to angio-
tensin II, inactivate bradykinin and produce active endothelin
The endothelium
from big endothelin. Normally, the endothelium, platelets and
The vascular endothelium plays an active role in the control of neutrophils will interact homeostatically. It is well known that
haemostasis and thrombosis (Table 1). It produces prostacyclin denudation of the endothelium will result in thrombosis;
© 1996 Journals of Reproduction and Fertility
1359-6004/96 $8.50108 F. Lyall and I. A. Greer
Table 1. Endothelial cell products and their main roles in regulating vascular homeostasis
Endothelial cell product Secreted Surface Function
expressed/bound
Prostacyclin + Platelet and neutrophil inhibition
Vasodilator
Nitric oxide + Platelet and neutrophil inhibition
Vasodilator
Endothelin + Vasoconstriction
Ectonucleotidases + Vascular tone, platelet function
Platelet-activating factor + + Platelet activation
Leucocyte function
von Willebrand factor + + Promotes coagulation, platelet adhesion
Tissue factor + Promotes coagulation
Binding sites for coagulation + Promotes coagulation
factors Va, Xa, IXa
Thrombomodulin + + Inhibits coagulation
Glycosaminoglycans + + Inhibits coagulation
Protein C, protein S + + Inhibits coagulation
Tissue plasminogen activator + + Increases fibrinolysis
Plasminogen activator inhibitor + + Inhibits fibrinolysis
Cell adhesion molecules: + + Promotes leucocyte adhesion
VCAM-1, P-Selectin,
ICAM-2, E-Selectin, PECAM-1
Cytokines, eg interleukin (IL)-1, + Numerous effects on immune system
IL-6, IL-8, colony-stimulating factors
VCAM: vascular endothelial cell adhesion molecule; ICAM: intercellular adhesion molecule; PECAM: platelet
endothelial cell adhesion molecule.
endothelial dysfunction may have similar effects and could the increase in blood pressure results from an increase in sys-
transform the endothelium from a nonthrombogenic to a temic vascular resistance. Normal pregnancy is also character-
thrombogenic surface. The endothelium can also regulate ized by decreased reactivity to pressor stimuli.
neutrophil and platelet adhesion and activation through the What is the evidence that nitric oxide is involved in the cir-
expression and secretion of cell adhesion molecules. culatory changes of normal and indeed abnormal pregnancy?
Furthermore, cytokines acting on or released by endothelial The synthesis of NO and cGMP increases from prepregnant
cells can affect many aspects of endothelial function. amounts during gestation in rats (Conrad et al., 1993). Plasma
Endothelial cells can also modify low density lipoproteins concentrations and urinary excretion of cGMP are also increased
(LDL), giving rise to damaging oxidized LDL, and damaged during human pregnancy (Kopp et al., 1977). Excess production
endothelial cells are also a source of growth factors. of NO may also explain the blunted pressor response to nor-
adrenaline seen during normal pregnancy. Although infor-
mation on the role of NO in human pregnancy is limited, it is
Nitric oxide
known that NO contributes to vascular tone in the human pla-
Nitric oxide (NO) plays an important role in the control of cental villus vascular tree (Myatt et al., 1991). The human feto-
systemic blood pressure (Knowles and Moncada, 1994). The placental circulation is not innervated and vasoactive factors
endothelial nitric oxide synthase (eNOS) generates NO con- such as NO are likely to be important in maintaining feto-
tinually, which diffuses to the underlying smooth muscle, in- placental blood flow. An endothelial isoform of NOS has been
creasing cGMP production and thus mediating vasodilatation characterized in the human placenta and immunolocalized to
(Fig. 2). Nitric oxide is also an inhibitor of platelet and neutro- the endothelium of umbilical, chorionic plate and stem villous
phil activation and impairment of its formation in the vessel vessels but not to terminal villous vessels in which there is no
wall will not only lead to neutrophil activation and vasocon- underlying smooth muscle (Myatt et al., 1993). Immunostaining
striction in the maternal circulation but will also favour platelet is also found in syncytiotrophoblast, but not in the underlying
adhesion, aggregation and the consequent release of vasocon- progenitor cytotrophoblast cells. Since it is the syncytiotropho-
strictor substances. blast that lines the placental surface and is in direct contact
During pregnancy a number of changes occur in the cardio- with maternal blood, NO produced by the syncytiotrophoblast
vascular system. Blood pressure declines in the first trimester, may prevent platelet and leucocyte adhesion within the inter-
reaches a nadir in midpregnancy and then slowly increases to villous space.
values comparable with those in the nonpregnant state. Cardiac In established pre-eclampsia, cardiac output is reduced and
output increases by 40% and this is maintained throughout the plasma volume is contracted, while systemic vascular resistance
pregnancy. The fall in blood pressure reflects a reduction in is noticeably raised. This raised systemic vascular resistance is
systemic vascular resistance. In the second half of pregnancy, not sympathetically mediated. The response to vasopressorVascular endothelium in pregnancy and pre-eclampsia 109
Coagulation pathways Coagulation inhibition pathways
XII Coagulation
XI VIIa Cell surface
XIIa
XIa TF
IX IXa IX
VIIIi
C4b-binding protein
VIII VIIIa VIIa protein S complex
X Xa X
V Va Vi Protein S
Prothrombin Thrombin Activated
Protein C
protein C
Fibrinopeptides
Thrombomodulin
Fibrinogen Fibrin
α2AP/α2M Fibrin degradation products Fibrinolysis
HRG Plasminogen Plasmin
PAI-1 PAI-1
tct-PA HMW-UK
PAI-1 Plasmin ProUK Kallikrein Prekallikrein
sct-PA
Endothelial cells XII, HMWK
Fig. 1. Simplified version of the pathways of coagulation activation and inactivation (pink background) and of the activators and inhibitors
of the fibrinolytic system (yellow background). Factor IX is activated by factor XIa or tissue factor (TF). Conversion of factor X to factor Xa
occurs by the action of factor IXa–VIII/VIIIa cell surface complex. Xa generates thrombin from prothrombin in the presence of Va
and activated platelets. Thrombin acts on fibrinogen releasing fibrinopeptides A and B. Activated protein C degrades factors V, VII and
VIII when they are bound to phospholipid. Binding of protein S to C4b-binding protein inhibits the anticoagulant effects of protein S.
sct-PA: single chain tissue plasminogen activator; tct-PA: two-chain tissue plasminogen activator; PAI-1: plasminogen activator inhibitor
type-1; HRG: histidine-rich glycoprotein; HMWK: high molecular weight kininogen; ProUK: Pro-urokinase urinary-type plasminogen acti-
vator; α2AP: α2-antitrypsin; α2M: α2-macroglobulin. Red arrows denote inhibition.
agents is also exaggerated. It has been hypothesized that an bradykinin is reduced in pregnancy-induced hypertension
imbalance in NO production may be related to these abnor- (Pinto et al., 1991). However, studies on relaxation responses in
malities. Studies in animals seem to support this hypothesis. maternal resistance arteries suggest that the NO-mediated com-
In pregnant rats, chronic blockade of NO synthesis increases ponent of endothelium-dependent relaxation is unaffected in
blood pressure, induces proteinuria and IUGR, and reduces ex- pre-eclampsia (McCarthy at al., 1993). Synthesis of NO can be
pansion of maternal plasma volume space (Molnar et al., 1994). determined indirectly by measuring concentrations of nitrites
In humans, however, the evidence is conflicting. The ability and nitrates, oxidation products of NO. Cameron et al. (1993)
of perfused umbilical vessels to release NO in response to showed that concentrations of urinary nitrites and nitrates in110 F. Lyall and I. A. Greer
Neutrophil
Platelet Blood
Agonist Shear stress NO
Ca2+
Receptor eNOS Endothelium
L-Arginine NO L-Citrulline
NO
cGMP
GTP Smooth muscle
Vasorelaxation
Fig. 2. Schematic diagram showing constitutive release of nitric oxide (NO) in endothelial cells. In endo-
thelial cells, shear stress and agonists such as acetylcholine, adenosine diphosphate, thrombin, bradykinin
and 5-hydroxytryptamine increase intracellular calcium and activate NO synthase (eNOS) to form NO
from L-arginine. The by-product from the reaction is L-citrulline. In blood, NO is readily oxidized by the
superoxide anion or bound to haemoglobin and to SH groups on albumin and thiols. NO readily diffuses
from the endothelium into the underlying vascular smooth muscle where it increases cGMP concen-
trations thus mediating vasorelaxation. NO also inhibits neutrophil and platelet activation at the endo-
thelial surface.
normal pregnant and hypertensive pregnant women were simi- endothelium of small vessels of the villous tree occurs in pre-
lar; however, in hypertensive women there was a direct cor- eclampsia (Myatt et al., 1995). In agreement with this, concen-
relation between urinary nitrite/nitrate excretion and the trations of nitrites in umbilical vein are also increased (Lyall
change in systolic blood pressure, which suggests that a com- et al., 1995a), supporting the hypothesis that increased NO
pensatory increase in NO synthesis occurs in pregnant women synthesis may be an adaptive response to increased blood flow
to maintain homeostasis. In agreement with this, serum con- in the uteroplacental circulation. In contrast, Wang et al. (1994)
centrations of nitrites are unaltered in the maternal circulation found no differences in the production of NO from placental
in pre-eclampsia (Lyall et al., 1995a). However, other studies tissues from women with pre-eclampsia, and Kovacs et al.
have reported reduced circulating concentrations of nitrites in (1994) reported that umbilical venous plasma concentrations
women with pre-eclampsia (Seligman et al., 1994). It may be of cGMP were reduced in women with pre-eclampsia and
that these discrepancies reflect the limitations of this assay, pregnancy-induced hypertension. The only study to investigate
which is affected by factors such as diet, or that larger studies enzyme activity showed that placental villous homogenates
are required to obtain more reliable data. Studies in vitro have from pregnancies complicated by pre-eclampsia and fetal
shown that endothelial cell nitrite production is higher after ex- growth retardation had lower activities of NOS than did nor-
posure to plasma from patients with pre-eclampsia compared mal pregnancies (Morris et al., 1995). In summary, generation
with plasma from normal pregnant women (Baker et al., 1995). of NO is increased in normal pregnancy (for a review of the
Nitric oxide synthesis can be inhibited by arginine analogues, role of NO in the uterus during pregnancy see Norman and
including Nω,Nω dimethylarginine (ADMA), which is present Cameron, 1996); however, convincing evidence that NO plays
both in human plasma and urine and can be released from a role in the endothelial dysfunction of pre-eclampsia and other
endothelial cells in vitro. Concentrations of ADMA are in- hypertensive disorders of pregnancy remains contentious.
creased in patients with pre-eclampsia (Fickling et al., 1993).
Increased vascular resistance in the fetoplacental circulation is
Prostanoids
also a characteristic of pre-eclampsia and IUGR pregnancies.
Infusion of the NO donor, glycerol trinitrate (GTN) has been Prostacyclin (PGI2), a mainly endothelial-derived prostanoid,
shown to improve uterine artery blood flow in pregnancy, synthesized from arachidonic acid (Fig. 3) is a potent vaso-
whereas other vasodilators have only minor effects (Ramsay dilator, an inhibitor of platelet aggregation and a stimulator of
et al., 1994). Whether improving uterine artery blood flow will renin secretion. In contrast, thromboxane A2 (TXA2), which is
also improve maternal or fetal outcome remains to be estab- released by platelets and metabolized from endoperoxides by
lished. Results of studies on the fetoplacental unit are also thromboxane synthase, is a potent vasoconstrictor and platelet
conflicting. Increased immunostaining for eNOS in stem aggregating agent. Thus PGI2 and TXA2 have opposing effects
villous vessels and the appearance of eNOS staining in the on thrombosis and haemostasis.Vascular endothelium in pregnancy and pre-eclampsia 111
The pathological features of pre-eclampsia include vasocon-
striction, platelet consumption and low renin secretion. Women
Membrane phospholipid with AA
with pre-eclampsia are very sensitive to exogenous angiotensin
esterified to the number two position
II infusions when compared with normal pregnant women. The
insensitivity to angiotensin II seen in normal pregnancy can
be abolished by treatment with a cyclooxygenase inhibitor,
and enhanced by infusion of prostacyclin or prostaglandin E2
(Broughton-Pipkin et al., 1984). This suggests that in normal
pregnancy, angiotensin II may be balanced by the action of 1 2 PLA2
vasodepressor prostaglandins such as prostacyclin. A deficiency
of prostacyclin may therefore result in the angiotensin II sensi-
tivity seen in pre-eclampsia. Maternal vascular prostacyclin
production is reduced in pre-eclampsia (Bussolino et al., 1980). AA
Lipoxygenase
However, TXB2 production (TXB2 is the metabolite of TXA2) Cyclo-oxygenase
is increased (Wallenburg and Rotmans, 1982). The resulting
imbalance between the prostanoids, prostacyclin and throm- Leukotrienes HETEs
boxane is likely to contribute to the enhanced platelet reactivity Endoperoxides
and vascular damage seen in pre-eclampsia. PGG2 / PGH2
On the fetal side, production of prostacyclin from cord ves-
sels is reduced in pre-eclampsia (Walsh, 1985). Furthermore, PGI2 synthase Thromboxane synthase
placentae from these pregnancies have been shown to produce
more thromboxane A2 and less prostacyclin than those from
normal pregnancies (Walsh, 1985). Umbilical arteries from
PGI2 PGE2 TXA2
pregnancies complicated by pre-eclampsia are unresponsive to
(endothelium) PGF2α (platelet)
a stimulus of prostacyclin production when compared with nor-
mal umbilical arteries (McLaren et al., 1987). Since the umbilical PGD2
artery is not innervated, it may depend on humoral control of
blood flow by prostanoids to maintain the low pressure–high
flow fetoplacental circulation. Failure to produce prostacyclin in Fig. 3. Biosynthetic pathway for prostacyclin and thromboxane.
response to physiological stimulation may result in increased Arachidonic acid (AA), cleaved from membrane phospholipids by
umbilical artery resistance due to vasoconstriction, especially in phospholipase A2 (PLA2), is the substrate for the cyclo-oxygenase
the face of increased thromboxane production by the placenta. pathway to form prostacyclin (PGI2), thromboxane A2 (TXA2) and
The deficiency of prostacyclin and the resulting prostanoid im- other prostanoids. AA is also the substrate for the lipoxygenase
balance may also allow vascular damage to occur unchecked. pathway to form leukotrienes and hydroxytetraeicosenoic acids
The interactions between PGI2 and TXA2 have provided the (HETEs). PGI2 is produced mainly by the endothelium and TXA2 in
rationale for low dose aspirin therapy as a treatment for pre- platelets.
eclampsia. However, the biggest trials to date suggest that
aspirin has limited benefit in treating or preventing pre-
eclampsia (reviewed in Lyall and Greer, 1994).
Neutrophil activation
Neutrophils contribute to vascular damage in nonpregnant
Platelets
individuals. Activated neutrophils release substances that can
Platelets play a crucial role in the pathophysiology of pre- mediate vascular damage, including the contents of neutrophil
eclampsia by promoting vascular damage and obstruction, granules such as elastase and other proteases. Toxic oxygen
leading to tissue ischaemia and further damage (Greer, 1992). species are released, and can produce membrane lipid per-
There is considerable evidence implicating platelets in the oxidation, lysis of endothelial cells, and increased vascular
pathophysiology of pre-eclampsia. The circulating platelet permeability and reactivity. However, before neutrophils and
count is reduced (Redman et al., 1978), reflecting a reduced other leucocytes can mediate vascular damage, they must first
platelet lifespan. The reduction in platelet count appears to be undergo a series of cellular events to adhere to the endothelial
due to increased platelet consumption associated with low surface (Harlan and Liu, 1992). They roll along the endothelial
grade disseminated intravascular coagulation. The platelet surface of the vessel wall and, at specific sites, become securely
specific protein β-thromboglobulin, a marker of platelet acti- flattened before passing into the subendothelial space (Fig. 4a).
vation in vivo, is also increased (Socol et al., 1985). This cor- Adherence of neutrophils to the endothelium is mediated by
relates with proteinuria and serum creatinine (Socol et al., cell adhesion molecules expressed on the endothelium and the
1985), and suggests a link between platelet activation and renal circulating leucocytes. The majority of cell adhesion molecules
microvascular damage. Increased platelet thromboxane A2 identified fall into one of four families: the immunoglobulin
production also occurs in pre-eclampsia (Wallenburg and superfamily, the integrins, the selectins and the cadherins; the
Rotmans, 1982). Delacretaz et al. (1995) reported reduced NOS former three being important in leucocyte–endothelial inter-
activity in platelets from women with pre-eclampsia and actions (Fig. 4b). On the endothelial surface, the major cell
suggested that this leads to enhanced vasoconstriction. adhesion molecules involved in leucocyte recruitment to the112 F. Lyall and I. A. Greer
(a) (b)
Neutrophil Endothelium
Selectin
NH2 Lectin EGF CRD CD COOH
Capture and rolling
Flattening Extravasation
Mg
α Mg β
Mg
Cell adhesion Leukotrienes S S
Integrin
molecule • Vasoconstriction S S
• Increase vascular
permeability
Free radicals Proteases (e.g. elastase)
• Increase vascular • Loss of glycosaminoglycans
permeability • Inactivation of enzymes for
• Membrane lipid prostacyclin production Immunoglobulin
peroxidation • Destroy integrity of
NH2 Ig1 Ig2 Ig3 Ig4 CD COOH
• Destroy endothelial endothelial cells and
cells basement membrane
Fig. 4. (a) Simplified representation of how cell adhesion molecules mediate neutrophil adhesion to the endothelium. (b) Schematic represen-
tation of the three major classes of cell adhesion molecules involved in leucocyte–endothelial interactions. Selectins are characterized by an
N-terminal lectin region, an epidermal growth factor-like domain (EGF), a number of units homologous to complement binding proteins
(CRD) and decay accelerating factor, a transmembrane domain and a short cytoplasmic tail (CD). Selectins have been named after the cell
type in which each molecule was first described: L-selectin (leucocyte), E-selectin (endothelial) and P-selectin (platelets). The lectin domain
interacts with carbohydrate structures on the cells that it binds to. Selectins are involved in leucocyte rolling. Integrins are a large family of
noncovalently linked heterodimeric glycoproteins, some of which are ligands for immunoglobulins. Each heterodimer is composed of a non-
covalently linked α chain and β chain. The β chain contains a large loop stabilized by disulfide bonds and α chains contain divalent cation
binding sites. Integrins are thought to immobilize leucocytes that are rolling, leading to spreading on the endothelial surface. The im-
munoglobulin family include a number of cell membrane glycoproteins with structural homology to antibodies. This family, which includes
platelet endothelial cell adhesion molecule 1 (PECAM-1), vascular cell adhesion molecule 1 (VCAM-1) and intercellular adhesion molecule 1,
2 and 3 (ICAM-1, -2 and -3), shares the immunoglobulin domain composed of 970–1100 amino acids arranged in a sandwich of two sheets
of anti-parallel β strands stabilized by a central disulfide bond.
endothelium include E-selectin and P-selectin, intercellular ad- to the vascular lesions noted in pre-eclampsia, for example
hesion molecule 1 and 2 (ICAM-1 and ICAM-2) and vascular in the placental bed. Elastase positive neutrophils can be
endothelial cell adhesion molecule 1 (VCAM-1). E-selectin, found in significantly increased numbers in the decidua of
VCAM-1 and ICAM-1 are either not or only minimally ex- the placental bed in women with pre-eclampsia, and this cor-
pressed on endothelial cells, but expression can be upregulated relates with plasma urate, an established marker of disease
by certain pro-inflammatory cytokines, such as tumour necro- activity (Butterworth et al., 1991). In addition to directly bring-
sis factor α (TNF-α) and interleukin (IL-1) (see Haskard, 1994 ing about endothelial damage, neutrophils will interact with
for a detailed review). Cell adhesion molecules can also be shed platelet, coagulation and complement systems. Since increased
from the endothelial surface and so exist as circulating forms. expression of cell adhesion molecules is associated with dis-
Circulating concentrations of adhesion molecules appear to re- eases involving leucocyte activation, the possibility arises that
flect their endothelial expression. Increased tissue expression cell adhesion molecules may be involved in the neutrophil
and increased circulating concentrations of endothelial ad- activation that occurs in pre-eclampsia. In support of this,
hesion molecules are also associated with diseases involving circulating concentrations of the cell adhesion molecules
endothelial damage and leucocyte activation. E-selectin and VCAM-1 are higher in the circulation of women
Neutrophils are activated in pre-eclampsia. Concentrations with pre-eclampsia compared with that of non-pregnant
of neutrophil elastase, a marker of neutrophil activation in vivo, women (Lyall et al., 1994; Lyall and Greer, 1995b). Furthermore,
are raised in pre-eclampsia, but this increase is confined to this effect appears to be confined to the maternal circulation,
the maternal circulation. This correlates with the increase since surface expression of these cell adhesion molecules is
in plasma von Willebrand factor and is associated with an similar in placentae obtained from pregnancies complicated
increase in endothelial endothelin concentrations (Greer et al., by pre-eclampsia and from normal pregnancies (Lyall et al.,
1991). Neutrophil activation may therefore contribute directly 1995b). Although the mechanisms of neutrophil activationVascular endothelium in pregnancy and pre-eclampsia 113
are not known, pro-inflammatory cytokines can activate allowing inhibition of platelet activation. Endothelins can cause
neutrophils and increase expression of cell adhesion molecules release of tissue plasminogen activator leading to increased
on endothelial cells. Circulating concentrations of the cytokine fibrinolytic activity. There are many reports describing in-
IL-6 are increased in plasma of women with pre-eclampsia creased circulating concentrations of endothelin in women
(Greer et al., 1994; Vince et al., 1995). Concentrations of TNF-α with pre-eclampsia (Taylor et al., 1990), and these changes cor-
and its soluble receptors are also increased in pre-eclampsia, relate with von Willebrand factor and fibronectin concen-
although increases in TNF-α may be linked to an extreme trations (Greer et al., 1991). These data are in keeping with the
form of this disease associated with very low platelet counts extent of the endothelium damage and dysfunction that occurs
(HELLP syndrome) (Greer et al., 1994; Vince et al. 1995). in this disorder.
Increased concentrations of IL-1 receptor antagonist, a nat-
urally occurring inhibitor of IL-1, also occur in pre-eclamspia,
Coagulation changes and endothelial dysfunction
suggesting a protective mechanism to counteract the effects
of IL-1 (Greer et al., 1994). Blood coagulation consists of a complex series of events that
Pre-eclampsia is also associated with a factor that enhances give rise to insoluble fibrin. The fibrinolytic enzyme system is
superoxide production from neutrophils (Tsukimori et al., the physiological mechanism that removes this fibrin (Fig. 1).
1993). High concentrations of reactive oxygen species can in- Clearly an imbalance between these two processes may lead to
hibit cyclo-oxygenase and prostacyclin synthase, thus inhibit- inappropriate thrombosis. Activation of the coagulation cas-
ing prostacyclin production. High concentrations of reactive cade is usually associated with activation of the fibrinolytic
oxygen species can reorientate the arachidonic acid pathway in system, and this is true for pre-eclampsia (Davies and Prentice,
the cell away from the production of prostacyclin towards 1992). Widespread deposition of fibrin associated with vascular
thromboxane A2. Furthermore, plasma concentrations of anti- damage, such as acute atherosis in the placental bed or
oxidants, which may reflect increased activity of reactive glomerular endotheliosis, has long been known to be a patho-
oxygen species, are also reduced in women with pregnancy- logical feature of pre-eclampsia and suggests that the coagu-
induced hypertension and these positively correlate with lation system is activated (Davies and Prentice, 1992; Greer,
prostaglandins, supporting a role for reactive oxygen species 1992). This probably represents a secondary phenomenon
in abnormal PGI2/TXB2 production (Chen et al., 1993). Thus, consequent upon vascular damage. Routine coagulation tests
neutrophil activation may account for the necrotizing arteri- are essentially normal, unless pre-eclampsia is complicated by
opathy of pre-eclampsia and may also explain several other full blown disseminated intravascular coagulation (Davies and
features of the disease, such as prostacyclin deficiency and en- Prentice, 1992). Increased concentrations of fibrinopeptide A
hanced thromboxane production. suggest that fibrinogen breakdown occurs in severe disease.
Fibrinogen itself also increases in hypertensive compared with
normal pregnancy, although this may simply be an acute phase
Lipids, vascular endothelial damage and pre-eclampsia
reactant increasing in response to the disease in general. There
There is much evidence linking hyperlipidaemia to endothelial is an increase in Factor VIIIc activity, but the increase in von
dysfunction in nonpregnant women (Stewart and Monge, Willebrand factor antigen is greater. Factor VIII is produced
1993). Normal pregnant women have hyperlipidaemia and by the liver, while von Willebrand factor is synthesized by the
some studies suggest that this may be enhanced in pre- vascular endothelium and increases after endothelial damage.
eclampsia (Maseki et al., 1981), suggesting that abnormal lipid The most precise assays of plasminogen activators and their
metabolism may have a role in this disorder. Furthermore, inhibitors have shown unchanged plasma plasminogen acti-
lipid peroxide products are increased in serum of women with vator, but increased concentrations of tissue plasminogen
pre-eclampsia (Maseki et al., 1981) and can inhibit prostacyclin activator in plasma of women with pre-eclampsia (Estelles et al.,
synthase but not thromboxane synthase. Women with pre- 1987). This may be due to stimulation of or damage to the
eclampsia also have a higher mean titre of autoantibodies to endothelium. This increase in tissue plasminogen activator is
oxidized low-density lipoproteins (Branch et al., 1994). accompanied by an increase in plasminogen activator in-
One of the key events in the pathogenesis of atherosclerotic hibitors 1 and 2 (Estelles et al., 1987). Plasminogen activator
lesions is the focal accumulation of lipid- (in particular the inhibitor 2 is produced only from the placenta and may again
oxidized form of low density lipoprotein) laden foam cells reflect placental vascular damage and predispose to local
(macrophages) beneath an intact endothelial lining. In pre- thrombosis by local inhibition of fibrinolysis in the abnormal
eclampsia, decidual vessels show fibrinoid necrosis of the vessels of the placental bed. It should be noted that all studies
vessel wall and focal accumulation of lipid-laden macrophages, have not been consistent.
similar to the situation in atherosclerosis, suggesting that The increase in fibrinopeptide Bβ1-42 provides additional
enhanced lipid peroxidation may be involved in the foam cell evidence of fibrinolytic activation. Plasminogen and the inhib-
formation. itor of plasmin, α2-antiplasmin, have also been found to be re-
duced (Davies and Prentice, 1992) in keeping with fibrinolytic
activation. This increase in fibrinolysis may be a response to
Endothelins
intravascular coagulation, which may be prevented from reach-
The endothelins are the most potent vasoconstrictors known, ing its full potential by the concomitant increase in intravascu-
exerting their vasoconstricting effects via ETA receptors on lar inhibitors of plasminogen activation.
smooth muscle cells. By acting on ETB receptors, endothelins There are no major changes in most of the individual co-
can release NO and prostacyclin from the endothelium, agulation factors (reviewed in Greer, 1992), suggesting that, in114 F. Lyall and I. A. Greer
Normal pregnancy Maternal blood
Radial artery
Uterine artery
Factors
Platelet/coagulation
activation
Basal artery
Pre-eclampsia Syncytiotrophoblast
Endothelial Neutrophil
damage/dysfunction activation
Hypertension
Maternal circulation
Arcuate artery
Myometrium Decidua Placental villi
Fig. 5. Schematic representation of trophoblast invasion of spiral arteries. Broken lines indicate trophoblast invading the vessels. It has been
suggested that impaired invasion of spiral arteries in pregnancies complicated by pre-eclampsia results in release of a factor(s) into the
maternal circulation, causing widespread endothelial damage and dysfunction.
general, only minimal coagulation activation occurs, although significantly increases cellular fibronectin, an important medi-
this may progress to complete disseminated intravascular co- ator of platelet adhesion and aggregation (Taylor et al., 1991).
agulation in severe cases.
Diabetic pregnancy
The origins of endothelial dysfunction
Type 1 (insulin-dependent) diabetes mellitus (IDDM) is a
The aetiology of pre-eclampsia is likely to be found in early chronic autoimmune disease characterized by destruction of
pregnancy. In pre-eclampsia, the normal process of trophoblast the pancreatic β-cells. Although IDDM complicates fewer than
invasion of maternal spiral arteries is impaired (Pijnenborg 0.5% of all pregnancies, pregnancy in women with diabetes
et al., 1991). Furthermore, this impaired trophoblast invasion is associated with increased maternal morbidity due to factors
appears to be linked to a failure of the invading trophoblast cells such as increased caesarean section rate, polyhydramnios and
to express a class of integrin cell adhesion molecules (Zhou et al., pre-eclampsia. The mother may also be at risk of a deterio-
1993). Several lines of evidence suggest that impaired tropho- ration in microvascular complications; however, it appears
blast invasion and hence reduced placental perfusion may lead that background and possibly proliferative retinopathy im-
to release of a factor(s) that brings about widespread endo- proves after delivery. Similarly, although diabetic nephropathy
thelial cell activation, leading to the multisystem dysfunction may worsen in pregnancy, it tends to return to the pre-
that characterizes pre-eclampsia (Fig. 5). The nature of this factor pregnant state after delivery. These findings suggest that there
is unclear but, since it diminishes after delivery (Roberts et al., is a pregnancy-associated factor(s) that triggers deterioration
1991), it may be released from the placenta or could equally of such microvascular complications.
well be related to neutrophil activation. Incubation of endo- Platelet and neutrophil activation (Greer et al., 1989) also
thelial cells in vitro with sera from pre-eclamptic women also occur in diabetic pregnancy. Neutrophil activation is present inVascular endothelium in pregnancy and pre-eclampsia 115
nonpregnant diabetic women (Greer et al. 1989). There is also induced hypertension and growth retardation. In Haemostasis and Thrombosis
evidence of endothelial damage, as assessed by measurement in Obstetrics and Gynaecology pp 43–162 Eds IA Greer, AGG Turpie and
CD Forbes. Chapman and Hall, London
of von Willebrand factor in diabetic nephropathy (Stehouwer Delacretaz E, De Quay N, Waeber B, Vial Y, Schulz P-E, Burnier M,
et al., 1991). It may be that the pathophysiogical process that Brunner HR, Bossart H and Schaad NC (1995) Differential nitric oxide
mediates vascular damage in pre-eclampsia may also play a synthase activity in human platelets during normal pregnancy and pre-
role in endothelial damage in diabetic pregnancy. eclampsia Clinical Science 88 607–610
Estelles A, Gilabert J, Espana F, Aznar J and Gomez-Lechon MJ (1987)
Fibrinolysis in pre-eclampsia Fibrinolysis 1 209–214
Conclusions Fickling SA, Williams D, Vallance P, Nussey SS and Whitley G St J (1993)
Plasma concentrations of endogenous nitric oxide synthesis in normal
Endothelial damage and dysfunction are common features of pregnancy and pre-eclampsia Lancet 342 242–243
all of the pathological features of pre-eclampsia, stimulating the *Greer IA (1992) Pathological processes in pregnancy induced hypertension
and intrauterine growth retardation: ‘An excess of heated blood’. In
activation of platelets, neutrophils and the coagulation system, Haemostasis and Thrombosis in Obstetrics and Gynaecology pp 163-202
and promoting further vascular damage. Activation of platelets Eds IA Greer, AGG Turpie and CD Forbes. Chapman and Hall, London
and the coagulation system can cause endothelial damage Greer IA, Haddad NG, Dawes J, Johnston TA, Johnstone FD and Steel J
directly, and also indirectly by activation of neutrophils. Thus, (1989) Increased neutrophil activation in diabetic pregnancy and non-
pregnant diabetic women Obstetrics and Gynecology 74 878–881
endothelial damage, the platelets and coagulation system, and
Greer IA, Leask R, Hodson BA, Dawes J, Kilpatrick DC and Liston WA
neutrophils all interact. Once one of these systems is triggered, (1991) Endothelin, elastase and endothelial dysfunction in pre-eclampsia
a positive feedback loop will promote vascular damage. The Lancet i 558
trigger that initiates this vicious circle is unclear. It appears to Greer IA, Lyall F, Perera T, Boswell F and Macara LM (1994) Increased con-
originate in the placenta or uteroplacental bed and is probably centrations of cytokines interleukin-6 and interleukin-1 receptor antagonist
in plasma of women with pre-eclampsia: a mechanism for endothelial
linked to the failure of trophoblast invasion, which is charac- dysfunction? Obstetrics and Gynecology 84 937–940
teristic of the disease. This process leads to tissue ischaemia, Harlan JM and Liu DY (Eds) (1992) Adhesion: Its Role in Inflammatory Disease
which, in turn, activates the vicious circle described above to WH Freeman and Company, New York
produce widespread endothelial damage and dysfunction. Haskard DO (1994) Adhesive proteins. In Haemostasis and Thrombosis
pp 233-257 Eds AL Bloom, CD Forbes, DT Thomas and EGD Tuddenham.
Management of pre-eclampsia at present focuses on controlling
Longman Singapore Publishers (Pte) Ltd, Singapore
blood pressure but effective diagnosis and treatment will come Knowles RG and Moncada S (1994) Nitric oxide synthases in mammals
only as a result of a clearer understanding of the pathogenesis Biochemical Journal 298 249–258
of the disease. Kopp L, Paradiz G and Tucci R (1977) Urinary excretion of cyclic 3′5′-
guanosine monophosphate during and after pregnancy Journal of Clinical
The authors thank I. T. Cameron for his critical reading of the Endocrinology and Metabolism 44 590–594
Kovacs GA, Makary A, Peto J and Stenmetz G (1994) Deficiency of c-GMP
manuscript.
level in placental circulation in pregnancy-induced hypertensive dis-
orders: possibility of decreased endothelium-derived relaxing factor
References activity Hypertension in Pregnancy 13 163–169
*Lyall F and Greer IA (1994) Pre-eclampsia: a multifaceted vascular disorder
Key references are identified by asterisks. of pregnancy Journal of Hypertension 12 1339–1345
Baker PN, Davidge ST and Roberts JM (1995) Plasma from women with pre- Lyall F and Greer IA (1995a) Is pre-eclampsia a preventable disease? Recent
eclampsia increases endothelial cell nitric oxide production Hypertension 26 Advances in Obstetrics and Gynaecology 18 3–21
244–248 Lyall F and Greer IA (1995b) (Letter) The cell adhesion molecule VCAM-1 is
Bloom AL, Forbes CD, Thomas DT and Tuddenham EGD (Eds) (1994) selectively elevated in serum in pre-eclampsia: does this indicate the
Haemostasis and Thrombosis Longman Singapore Publishers (Pte) Ltd, mechanism of leucocyte activation? British Journal of Obstetrics and
Singapore Gynaecology 102 173–174
Branch DW, Mitchell MD, Miller E, Palinski W and Wiztum JL (1994) Pre- Lyall F, Greer IA, Boswell F, Macara LM, Walker JJ and Kingdom JCP
eclampsia and serum antibodies to oxidised low-density lipoprotein Lancet (1994) The cell adhesion molecule VCAM-1 is selectively elevated in serum
343 645–646 in pre-eclampsia: does this indicate the mechanism of leucocyte activation?
Broughton-Pipkin F, Morrison R and O’Brien PMS (1984) Effects of prosta- British Journal of Obstetrics and Gynaecology 101 485–487
cyclin on the pressor response to angiotensin II in human pregnancy Lyall F, Greer IA and Young A (1995a) Nitric oxide concentrations are in-
European Journal of Clinical Investigation 14 3 creased in the feto-placental circulation in pre-eclampsia. American Journal
Bussolino F, Benedetto C, Massobrio M and Comussi G (1980) Maternal of Obstetrics and Gynecology 173 714–718
vascular prostacyclin activity in pre-eclampsia Lancet ii 702 (letter) Lyall F, Greer IA, Boswell F, Young A, Macara LM and Jeffers MD (1995b)
Butterworth B, Greer IA, Liston WA, Haddad NG and Johnstone TA (1991) Expression of cell adhesion molecules in placentae from pregnancies com-
Immunocytochemical localization of neutrophil elastase in term placenta plicated by pre-eclampsia and intrauterine growth retardation Placenta 16
decidua and myometrium in pregnancy-induced hypertension British 579–587
Journal of Obstetrics and Gynaecology 98 929–933 McCarthy AL, Woolfson RG, Raju SK and Poston L (1993) Abnormal endo-
Cameron IT, van Papendorp CL, Palmer RMJ, Smith SK and Moncada S thelial function of resistance arteries from women with preeclampsia
(1993) Relationship between nitric oxide synthesis and increase in systolic American Journal of Obstetrics and Gynecology 168 1323–1330
blood pressure in women with hypertension in pregnancy Hypertension in McLaren M, Greer IA, Walker JJ and Forbes CD (1987) Reduced prosta-
Pregnancy 12 91–98 cyclin production by umbilical arteries from pregnancy complicated by
Chen G, Wilson R, Cumming G, Walker JJ, Smith WE and McKillop JH severe pregnancy induced hypertension Clinical and Experimental
(1993) Prostacyclin, thromboxane and antioxidant levels in pregnancy- Hypertension B6 365–374
induced hypertension European Journal of Obstetrics and Gynaecology and Maseki M, Nishigaki I, Hagihara M, Tomoda Y and Yagi K (1981) Lipid
Reproductive Biology 50 243–250 peroxide levels and lipid content of serum lipoprotein fractions of preg-
Conrad KP, Joffe GM, Krusznya H, Krusznya R, Rochelle LG, Smith RP, nant subjects with or without preeclampsia Clinica Chimica Acta 115 155–161
Chavez JE and Mosher MD (1993) Identification of increased nitric oxide Molnar M, Suto T, Toth T and Hertelendy F (1994) Prolonged blockade of
biosynthesis during pregnancy in rats Federation of American Societies for nitric oxide synthesis in gravid rats produces sustained hypertension, pro-
Experimental Biology Journal 7 566–571 teinuria, thrombocytopenia and intrauterine growth retardation American
*Davies JA and Prentice CRM (1992) Coagulation changes in pregnancy- Journal of Obstetrics and Gynecology 170 1458–1466116 F. Lyall and I. A. Greer Morris NH, Sooranna SR, Learmont JG, Poston L, Ramsey B, Pearson JD Journal of Obstetrics and Gynecology 171 944–948 and Steer PJ (1995) Nitric oxide synthase in placental tissue from normo- Socol ML, Weiner CP, Louis G, Rehnberg K and Rossi EC (1985) Platelet tensive, pre-eclamptic and growth retarded pregnancies British Journal of activation in pre-eclampsia American Journal of Obstetrics and Gynecology Obstetrics and Gynaecology 102 711–714 151 494–497 Myatt L, Brewer A and Brockman DE (1991) The action of nitric oxide in the Stehouwer CDA, Stroes ESG, Hackeng WHL, Mulder PGH and perfused human fetal–placental circulation American Journal of Obstetrics den Ottolander EJH (1991) Von Willebrand factor and development and Gynecology 164 687–692 of diabetic nephropathy in IDDM Diabetes 40 971–976 *Myatt L, Brockman DE, Eis ALW and Pollock JS (1993) Immunohisto- Stewart DJ and Monge JC (1993) Hyperlipidaemia and endothelial dysfunc- chemical localization of nitric oxide synthase in the human placenta tion Current Opinion in Lipidology 4 319–324 Placenta 14 487–495 Taylor RN, Varma M, Teng NNH and Roberts JM (1990) Women with pre- Myatt L, Eis ALW, Brockman DE, Greer IA and Lyall F (1995) Expression of eclampsia have higher plasma endothelin levels than women with normal endothelial nitric oxide synthase in placental villous tissue from normal, pregnancies Journal of Clinical Endocrinology and Metabolism 71 1675–1677 pre-eclamptic and intrauterine growth restricted pregnancies Journal of the Taylor RN, Casal DC, Jones LA, Varma M, Martin JN, Jr and Roberts JM Society for Gynecologic Investigation 2 259 (1991) Selective effects of preeclampsia sera on human endothelial cell pro- Norman JE and Cameron IT (1996) Nitric oxide in the human uterus Reviews coagulant protein expression American Journal of Obstetrics and Gynecology of Reproduction 1 61–68 165 1705–1710 Pijnenborg R, Anthony J, Davey DA, Rees A, Tiltman A, Vercruysse L and Tuskimori K, Maeda H, Ishida K, Nagata H, Koyanagi T and Nakano H Van Assche AV (1991) Placental bed spiral arteries in the hypertensive (1993) The superoxide generation of neutrophils in normal and pre- disorders of pregnancy British Journal of Obstetrics and Gynaecology 98 eclamptic pregnancies Obstetrics and Gynaecology 81 536–540 648–655 Vince GS, Starkey PM, Austgulen R, Kwiatkowski D and Redman CWG Pinto A, Sorrentino R, Sorrentino P, Sorrentino P, Guerritore T, Miranda L, (1995) Interleukin-6, tumour necrosis factor and soluble tumour necrosis Bondi A and Martinelli P (1991) Endothelial-derived relaxing factor re- factor receptors in women with pre-eclampsia British Journal of Obstetrics leased by endothelial cells of human umbilical vessels and its impairment and Gynaecology 102 20–25 in pregnancy-induced hypertension American Journal of Obstetrics and Wallenburg HCS and Rotmans N (1982) Enhanced reactivity of the platelet Gynecology 164 507–513 thromboxane pathway in normotensive and hypertensive pregnancies Ramsay, B De Belder A, Campbell S, Moncada S and Martin JF (1994) A with insufficient fetal growth American Journal of Obstetrics and Gynecology nitric oxide donor improves uterine artery diastolic blood flow in normal 144 523–528 early pregnancy and in women at high risk of pre-eclampsia European Walsh SW (1985) Pre-eclampsia: an imbalance in placental prostacyclin and Journal of Clinical Investigation 24 76–78 thromboxane production American Journal of Obstetrics and Gynecology 152 Redman CWG, Bonnar J and and Beilin LJ (1978) Early platelet con- 335–340 sumption in pre-eclampsia British Medical Journal 1 467–469 Wang Y, Walsh SW, Parnell R and Han JTI (1994) Placental production of *Roberts JM, Taylor RN and Goldfien A (1991) Clinical and biochemical nitric oxide and endothelin in normal and preeclamptic pregnancies evidence of endothelial cell dysfunction in the pregnancy syndrome Hypertension in Pregnancy 13 171–178 preeclampsia American Journal of Hypertension 4 700–708 Zhou Y, Damsky CH, Chiu K, Roberts JM and Fisher SJ (1993) Preeclampsia Seligman SP, Buyon JP, Clancy RM, Young BK and Abramson SB (1994) is associated with abnormal expression of adhesion molecules by invasive The role of nitric oxide in the pathogenesis of pre-eclampsia American cytotrophoblasts Journal of clinical Investigation 91 950–960
You can also read
