Changes in Endothelial Function Precede the Clinical
Disease in Women in Whom Preeclampsia Develops
Faisel Khan, Jill J.F. Belch, Maureen MacLeod, Gary Mires
Downloaded from http://hyper.ahajournals.org/ by guest on June 15, 2017
Abstract—Endothelial dysfunction is important in the pathophysiology of preeclampsia. No study has examined
endothelial function sequentially at different gestations before development of the clinical syndrome and after delivery
(to compare maternal from placental influences). We sought to determine whether endothelial function changes before
the clinical development of preeclampsia. We measured skin microvascular function using iontophoresis of acetylcholine and sodium nitroprusside, and laser Doppler imaging at 22, 26, 34 weeks’ gestation and 6 weeks postpartum in
women identified as being at increased risk of preeclampsia, based on uterine artery Doppler waveforms at 18 to 20
weeks, and controls with normal Doppler waveforms. Fifty-four women remained normotensive and preeclampsia
developed in 15. In normotensive and preeclamptic women, acetylcholine responses were augmented during pregnancy
compared with postpartum responses (P⬍0.001). Sodium nitroprusside responses were augmented during pregnancy
compared with those postpartum (P⬍0.005) in preeclamptic women only. Microvascular responses were augmented in
women in whom preeclampsia developed, compared with those in normotensive women, at 26 and 34 weeks for
acetylcholine (P⬍0.05 and P⬍0.001, respectively) and at 22 and 26 weeks for sodium nitroprusside (P⬍0.05 and
P⬍0.02, respectively). Postpartum acetylcholine and sodium nitroprusside responses were not significantly different
between preeclamptic and normal women. Microvascular responses are enhanced during pregnancy in women in whom
preeclampsia develops to a level above that seen in normotensive women. These changes precede the onset of clinical
disease and might be related to a compensatory increased sensitivity of the microcirculation to nitric oxide.
(Hypertension. 2005;46:1123-1128.)
Key Words: endothelium-derived factors 䡲 hypertension 䡲 microcirculation 䡲 nitric oxide
䡲 preeclampsia 䡲 pregnancy
P
pregnant women.6 – 8 Conversely in the microcirculation, endothelium-dependent vasodilatation is increased in women
who have PE to levels over and above those seen in normal
pregnancy.9 After pregnancy, however, both arterial and
microvascular endothelial functions are diminished in women
who had PE.10 –12 This suggests that either endothelial dysfunction is present before pregnancy and predisposes women
to PE, or that PE induces long-term changes in endothelial
function, which could have implications for development of
cardiovascular disease in later life.
There is no study however, that has examined vascular
responses sequentially at different gestations before the clinical syndrome of PE develops and after delivery (to compare
maternal from placental influences), and compared these
changes to those in women who remain normotensive. The
purpose of this study, therefore, was to measure endothelial
function at 22, 26, and 34 weeks’ gestation and 6 weeks
postpartum in women identified as being at increased risk for
PE, based on uterine artery Doppler waveforms at 18 to 20
weeks, and control subjects with normal Doppler waveforms.
reeclampsia (PE) continues to be a leading cause of
maternal and perinatal morbidity and mortality. Characteristic hemodynamic changes occur during normal human
pregnancy, which include peripheral vasodilatation, reductions in total vascular resistance, and decreased arterial blood
pressure. The precise reasons for such changes are not clear,
but recent evidence points to changes in endothelial function
and nitric oxide activity as contributory factors.1,2
In PE there is accumulating evidence for a pathogenic
model whereby deficient trophoblast invasion of the maternal
spiral arteries leads to a poorly perfused feto-placental unit.3
This results in secretion of a factor(s) by the placenta into the
maternal circulation, which activates the vascular endothelium.4,5 However, although endothelial dysfunction appears to
be a key player in the pathophysiology of PE, there appears to
be a difference in the way in which endothelial damage is
expressed depending on the particular vascular bed studied.
For example, arterial endothelial function, assessed using
ultrasound measurements of flow-mediated dilatation, is diminished in women who have PE compared with normal
Received July 11, 2005; first decision July 28, 2005; revision accepted September 1, 2005.
From the Vascular Diseases Research Unit (F.K., J.J.F.B.), The Institute of Cardiovascular Research and Maternal and Child Health Sciences (M.M.,
G.M.), Ninewells Hospital and Medical School, University of Dundee, Dundee, Scotland, UK.
Correspondence to Dr Faisel Khan, Vascular Diseases Research Unit, The Institute of Cardiovascular Research, Ninewells Hospital and Medical
School, Dundee DD1 9SY, Scotland, UK. E-mail [email protected].
© 2005 American Heart Association, Inc.
Hypertension is available at http://www.hypertensionaha.org
DOI: 10.1161/01.HYP.0000186328.90667.95
1123
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Hypertension
November 2005
Outline of the experimental design. Reference to Table 1 indicates the number of
women in each outcome group according
to Doppler waveforms at 18 to 20 weeks’
gestation.
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We chose uterine arterial notching as a means of identifying
a cohort of women at increased risk of PE based on the
findings from a previous study that demonstrated a relative
risk of early onset PE of 26.2 (95% CI, 11.0 to 62.4) in
women with bilateral uterine arterial notching at 18 to 20
weeks’ gestation.13 We sought to determine whether changes
in endothelial function in PE occur before the clinical
development of the disease and whether such changes persist
after delivery.
Methods
Study Group and Outcome Definitions
An outline of the experimental design is shown in Figure 1, and
Table 1 shows the sample distribution of subjects into subsequent
groupings. Uterine arterial waveform analysis is routinely performed
at 18 to 20 weeks’ gestation at Ninewells Hospital, Dundee, and was
used as a screening test to identify a cohort of women at high risk for
an adverse pregnancy outcome.13 Women in whom bilateral uterine
arterial notching was identified at this gestation and control women
(with normal Doppler waveforms) were recruited into the study.
TABLE 1. Outcome of Pregnancy in Normal and Abnormal
Doppler Groups
Outcome Group
Normal outcome
Normal Doppler (n⫽30)
Notched (n⫽63)
20 (66.7%)
34 (53.9%)
Preeclampsia⫾IUGR
4 (13.3%)
11 (17.5%)
Gestational hypertension⫾IUGR
1 (3.3%)
8 (12.7%)
Normotensive IUGR
5 (16.7%)
10 (15.9%)
37.5 (35–39)
34.0 (31–37)
Gestation PE diagnosed (wk)*
IUGR indicates intrauterine growth restriction; PE, preeclampsia.
*There was no significant difference between gestation for diagnosis of PE
between the normal and notched Doppler groups (P⫽0.89).
Women with any underlying condition likely to compromise renal
function, such as diabetes or renal disease, were excluded from the
study. PE was defined as the presence of a systolic pressure
ⱖ140 mm Hg or a diastolic pressure of ⱖ90 mm Hg on ⱖ2 separate
occasions after week 20 of pregnancy in a woman who was
normotensive at booking (first trimester) and 6 weeks postnatally, in
the presence of significant proteinuria (either ⬎300 mg/L in a
24-hour collection or ⱖ2⫹ on a voided random urine sample in the
absence of urinary tract infection).14 Gestational hypertension was
defined as hypertension arising de novo in pregnancy without
proteinuria.14
The individualized birth weight ratio was used to define intrauterine growth restriction; individualized birth weight ratio corrects birth
weight for gestational age, taking into account confounding variables
of maternal height and weight, ethnic origin, parity, and infant sex
and was calculated using the UK Perinatal Institutes online calculator.15 Pregnancies with an individualized birth weight ratio ⬍10
were defined as growth-restricted.
The study was approved by the Tayside Committee on Medical
Research Ethics and conducted according to the principles outlined
in the Declaration of Helsinki. All subjects gave written informed
consent to their participation.
Microvascular Function
Measurements of microvascular function were performed at 22, 26,
and 34 weeks’ gestation, and at 6 weeks after delivery in a laboratory
set at 22⫾1°C. Participants were seated with their arms supported at
heart level. We assessed forearm microvascular function, as described previously,16 by measuring skin vascular responses to iontophoresis of acetylcholine (ACh; Sigma-Aldrich Co. Ltd) and
sodium nitroprusside (SNP; David Bull Laboratories). Iontophoresis
is a drug-delivery method that stimulates the migration of charged
ions across the skin noninvasively and without inducing systemic
effects. We used a delivery current of 100 ␮A and administered each
drug as a successive accumulation of 10-, 20-, 40-, and 80-second
doses, ie, effectively, 1, 2, 4, and 8 millicoulomb (mC). Using a
current of 100 ␮A and large-diameter electrodes does not elicit
Khan et al
TABLE 2.
Characteristics of Subject Groups
Variable
Normal (n⫽54)
Preeclampsia (n⫽15)
Endothelial Dysfunction in Preeclampsia
1125
Spearman-rank method. In all cases, significance was acknowledged
if the probability of a type-1 error was ⬍5% (ie, P⬍0.05).
Booking systolic BP (mm Hg)
112⫾12
117⫾8
Results
Booking diastolic BP (mm Hg)
67⫾8
69⫾8
Maximum systolic BP (mm Hg)
122⫾11
150⫾15*
Maximum diastolic BP (mm Hg)
78⫾7
99⫾9*
Gestation at delivery (wk)
36.4⫾4.1
35.3⫾3.4*
Birth weight (g)
3417⫾541
2509⫾1108*
Table 1 shows the pregnancy outcome for the notched and
normal Doppler waveform groups. The mean gestation time
for the onset of PE in the notched group was earlier than in
the normal Doppler group but the difference was not statistically significant.
Table 2 shows the clinical characteristics of women with
normal and preeclamptic pregnancies. Fifty-four women had
a normal pregnancy (mean age, 27.4; range, 15 to 37 years)
and PE developed in 15 women PE (mean age, 25.3; range,
20 to 31 years). In the PE group the maximum recorded blood
pressure was in all cases within 4 days of delivery (mean, 2.4
days; range, 1 to 4 days).
*P⬍0.001.
Values are mean⫾SEM.
Downloaded from http://hyper.ahajournals.org/ by guest on June 15, 2017
vasodilatation via nonspecific galvanic effects, because a low charge
density (maximum of 2.5⫻10⫺2 mC/mm2) is generated.17
Microvascular skin blood flow was assessed using laser Doppler
imaging (moorLDI; Moor Instruments Ltd). This technique works by
scanning a 2-mW helium–neon laser across the surface of the skin.
Light that is backscattered from moving erythrocytes undergoes a
shift in frequency proportional to their velocity, according to the
Doppler principle. The resulting color-coded image represents skin
blood flow over the scan area; a relative measure called the laser
Doppler flux. Baseline scans of skin perfusion (without drug delivery) were taken before the iontophoresis protocol was administered.
The median laser Doppler flux over the baseline and drug-delivery
site was calculated for each image using dedicated image-processing
software (Moor Instruments Ltd). For each dose response, the mean
of the 2 highest stable flux values was calculated, and this was
divided by the baseline measurement to give a ratio representing the
change in flow.
This combination of iontophoresis and laser Doppler imaging has
been used successfully by us and others in many studies,16 –18 and
good reproducibility of the technique has been confirmed.19,20 A
recent study by Hansell et al showed that skin microvascular
responses to iontophoretically applied ACh significantly correlated
with flow-mediated dilatation in the brachial artery.21
All measurements and calculations were performed by a researcher who was blinded as to whether the subject was normotensive or had PE.
Statistical Analysis
Statistical analysis was performed using SPSS 12.0 for Windows.
Results are presented as means⫾SEM. Data for microvascular
responses were not normally distributed and were therefore logtransformed to achieve normality. Differences in vascular responses
at different time points within subject groups, and between normal
and preeclamptic groups, were tested using ANOVA for repeated
measures, followed by modified post hoc t tests when a significant
difference was found. Correlations were performed using the
Comparison of Vascular Responses
There were no significant differences in vascular responses to
ACh and SNP between women with normal and abnormal
Doppler waveforms at any time point (Table 3).
Baseline skin perfusion (mean⫾SE in arbitrary perfusion
units [PU]) was not significantly different between normal
and preeclamptic women at 22 weeks (55.5⫾1.9 versus
52.5⫾3.0 PU, respectively), 26 weeks (56.4⫾2.1 versus
51.6⫾2.6 PU), 34 weeks (53.1⫾1.8 versus 50.9⫾4.3 PU),
and postpartum (51.6⫾1.9 versus 58.8⫾4.0 PU).
In women with normal pregnancies, vascular responses to
ACh were not significantly different at 22, 26, and 34 weeks
but were significantly enhanced compared with postpartum
responses (ANOVA P⬍0.001, P⬍0.001, and P⬍0.05, respectively) (Table 4). Post-hoc analysis comparing postpartum responses with those at 22 and 26 weeks showed
significant differences at doses of 2, 4, and 8 mC (P⬍0.01).
For comparisons between postpartum responses and those at
34 weeks, significant differences were found at 2 mC
(P⬍0.05) and at 4 and 8 mC (P⬍0.01). Peak ACh responses
were 13% higher at 34 weeks compared with postpartum
responses. In contrast, SNP responses were similar at all time
points (Table 4).
In preeclamptic women, there was a progressive increase in
ACh responses from 22 to 26 and 34 weeks (ANOVA,
P⬍0.01 for both), followed by a decrease postpartum. Post-
TABLE 3. Vascular Responses (Expressed as a Ratio of Response Over Baseline) to ACh and SNP in Normal Pregnant
Women (nⴝ30) and in Those With Bilateral Artery Notching (nⴝ63)
Ach
Time
22 weeks
26 weeks
34 weeks
Postpartum
SNP
1 mC
2 mC
4 mC
8 mC
1 mC
2 mC
4 mC
8 mC
Normal
2.6⫾0.2
4.7⫾0.3
5.9⫾0.3
7.0⫾0.3
1.7⫾0.2
2.6⫾0.3
4.2⫾0.4
5.6⫾0.4
Notched
2.6⫾0.1
4.4⫾0.2
6.0⫾0.3
7.0⫾0.3
1.8⫾0.1
3.0⫾0.2
4.6⫾0.3
6.2⫾0.3
Normal
2.7⫾0.2
4.8⫾0.3
6.4⫾0.3
7.4⫾0.4
1.8⫾0.2
2.7⫾0.2
4.0⫾0.3
5.7⫾0.3
Notched
2.7⫾0.1
4.7⫾0.2
6.2⫾0.3
7.2⫾0.3
2.0⫾0.1
3.4⫾0.2
5.1⫾0.2
6.6⫾0.3
Normal
2.2⫾0.2
4.0⫾0.3
5.6⫾0.3
6.7⫾0.3
1.6⫾0.1
2.4⫾0.2
4.1⫾0.3
5.9⫾0.4
Notched
2.7⫾0.2
5.0⫾0.3
6.7⫾0.3
8.1⫾0.3
2.0⫾0.1
3.0⫾0.2
5.0⫾0.3
7.1⫾0.3
Normal
1.8⫾0.1
3.5⫾0.2
5.1⫾0.3
6.6⫾0.3
1.5⫾0.1
2.4⫾0.2
3.8⫾0.3
5.9⫾0.3
Notched
2.2⫾0.1
3.8⫾0.2
5.2⫾0.2
6.4⫾0.2
1.7⫾0.1
2.8⫾0.2
4.3⫾0.3
6.0⫾0.3
Values are means⫾SE.
1126
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November 2005
TABLE 4. Comparison of Dose-Responses (Expressed as a Ratio of Response Over Baseline) by ANOVA to ACh and SNP
in Normotensive (nⴝ54) and PE Women (nⴝ15)
Acetylcholine
Time
22 weeks
26 weeks
34 weeks
Post partum
Sodium Nitroprusside
1 mC
2 mC
4 mC
8 mC
1 mC
2 mC
4 mC
8 mC
Normal
2.6⫾0.2
4.6⫾0.3
6.0⫾0.3
7.0⫾0.3
1.7⫾0.1
2.8⫾0.2
4.3⫾0.3
5.8⫾0.3储
PE
2.4⫾0.2
4.5⫾0.4
6.0⫾0.4
6.9⫾0.5§
1.6⫾0.1
3.0⫾0.4
4.8⫾0.6
6.7⫾0.6§
Normal
2.7⫾0.2
4.5⫾0.2
6.0⫾0.3
7.0⫾0.2储
1.9⫾0.1
2.9⫾0.2
4.3⫾0.3
5.7⫾0.3¶
PE
3.2⫾0.3
5.4⫾0.6
7.1⫾0.7
8.5⫾0.9
2.3⫾0.4
4.0⫾0.6
6.6⫾0.9
8.1⫾0.8†
Normal
2.4⫾0.2
4.2⫾0.3
5.8⫾0.3
7.1⫾0.3¶
1.8⫾0.1
2.6⫾0.2
4.3⫾0.3
6.2⫾0.4
PE
3.2⫾0.4
6.2⫾0.9
7.9⫾1.0
8.8⫾1.0
1.9⫾0.2
3.1⫾0.4
5.2⫾0.7
6.7⫾1.0
Normal
2.0⫾0.1
3.6⫾0.2
5.0⫾0.3
6.3⫾0.3*
1.8⫾0.1
2.9⫾0.3
4.5⫾0.4
6.2⫾0.4
PE
2.3⫾0.2
4.0⫾0.4
5.5⫾0.5
6.6⫾0.5†
1.4⫾0.1
2.1⫾0.2
3.5⫾0.4
5.5⫾0.5‡
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Footnotes refer to comparisons of dose-responses. See Results text for post-hoc analyses at individual doses. Values are means⫾SE.
*Comparing postpartum ACh responses with those at 22, 26, and 34 weeks (P⬍0.001, P⬍0.001, and P⬍0.05, respectively) in normal women.
†P⬍0.001comparing postpartum ACh responses with those at 26 and 34 weeks in PE women.
‡P⬍0.005 comparing postpartum SNP responses with those at 22, 26, and 34 weeks in PE women.
§P⬍0.01 comparing ACh responses at 22 weeks with those at 26 and 34 weeks, and SNP responses at 22 and 26 weeks in PE women.
储P⬍0.05 comparing normal vs PE responses at 26 weeks for ACh and at 22 weeks for SNP.
¶P⬍0.001 comparing normal vs PE responses at 34 weeks for ACh and at 26 weeks for SNP.
hoc analysis comparing responses at 22 weeks with those at
26 and 34 weeks showed significant differences at doses of 2,
4, and 8 mC (P⬍0.01). ACh responses at 26 and 34 weeks
were significantly greater than those postpartum (ANOVA,
P⬍0.001 for both). Post-hoc analysis showed significant
differences at doses of 2, 4, and 8 mC (P⬍0.001). Peak ACh
responses were 34% higher at 34 weeks compared with
postpartum responses. There was a smaller, but still significant, increase in SNP responses from 22 to 26 weeks
(ANOVA, P⬍0.01) (post-hoc differences at doses of 2, 4,
and 8 mC; P⬍0.01), followed by a reduction postpartum.
SNP responses at 22, 26, and 34 weeks were all significantly
greater than those post partum (ANOVA, P⬍0.005 for all).
Post-hoc analysis comparing post partum responses with
those at 22 and 34 weeks showed significant differences at
doses of 2, 4, and 8 mC (P⬍0.05), and at 26 weeks
differences were seen at doses of 2, 4, and 8 mC (P⬍0.001).
Vascular responses to ACh were not significantly different
between normal and preeclamptic women at 22 weeks and 6
weeks postpartum (Table 4). At 26 and 34 weeks, however,
ACh responses were significantly augmented in preeclamptic
women compared with normal women (ANOVA, P⬍0.05
and P⬍0.001, respectively). Post-hoc analysis at 26 weeks
showed significant differences at doses of 2, 4 (P⬍0.05), and
8 mC (P⬍0.01), and at 34 weeks at doses of 2, 4, and 8 mC
(P⬍0.01).
SNP responses were significantly augmented in preeclamptic women compared with control women at 22 and 26
weeks (ANOVA, P⬍0.05 and P⬍0.001, respectively) (Table
4). Post-hoc analysis at 26 weeks showed significant differences at doses of 4 and 8 mC (P⬍0.001) Postpartum SNP
responses were not significantly different between normal
and preeclamptic women (Table 4). None of the women had
clinically diagnosed PE at 26 weeks (mean gestation at onset,
34.9 weeks; range, 29 to 39 weeks).
Discussion
The findings of the present study in the microcirculation
show that normal pregnancy is associated with a steady
increase in endothelium-dependent vasodilatation, which returns to normal levels postpartum. In contrast, women in
whom PE develops show a progressive increase in endothelium-dependent vasodilatation during pregnancy to levels
over and above that seen in normal pregnancy. Endotheliumindependent, nitric oxide-mediated vascular responses are
also significantly increased during pregnancy in women in
whom PE develops. Importantly, these changes precede the
onset of clinical disease by weeks or months. We propose the
hypothesis that women in whom PE develops have an
increased sensitivity of the microcirculation to nitric oxide
during pregnancy, perhaps as a compensatory mechanism to
offset impaired placental perfusion.
During normal pregnancy, the augmented response to
acetylcholine, but not to sodium nitroprusside, suggests
enhanced production of endothelium-derived substances
rather than a generalized increased responsiveness of the
microvessels.22 Several mediators might be involved, such as
nitric oxide, prostacyclin, and endothelium-derived hyperpolarizing factor (EDHF).23,24 Our findings in the microcirculation are consistent with those seen in large vessels of
normal pregnant women.1
In women with PE, however, our findings in the microcirculation are not consistent with those in large vessels.
Flow-mediated dilatation is significantly reduced in women
with established PE compared with responses in normal
pregnant women.6 – 8 Brachial artery infusions of acetylcholine also produce diminished endothelium-dependent vasodilatation in established PE.25 Whether these changes are
transient during PE or more permanent could not be determined from these studies as all were performed at varying
single time points and no comparison was made with postpartum responses. Savvidou et al did find that changes in
endothelial function predated the development of PE by 10
weeks.7 In this regard, our results support this finding but the
way in which endothelial dysfunction is expressed during
pregnancy differs between large and small vessels.
Khan et al
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Enhanced microvascular responses to acetylcholine have
been shown previously in women who have PE by Davis et
al,9 but the time of onset of these changes could not be
determined from their study. In contrast to our study, they did
not find any differences in responses to sodium nitroprusside.
The reason for this could be that their measurements were
made using single point laser Doppler flowmetry as opposed
to imaging over a larger area as we did, which gives a better
representation of skin perfusion. They did, however, show a
trend toward an increased response but conducted their study
at a single time point only (between 34 and 36 weeks’
gestation) when the effects might not be as apparent. In
keeping with this, we saw a smaller difference in SNP
responses at 34 weeks’ compared with those at 22 and 26
weeks’ gestation in preeclamptic women.
Enhanced production of endothelium-derived substances
cannot be solely responsible for the changes seen in women
with PE because microvascular responses to both acetylcholine and sodium nitroprusside were significantly altered. It is
likely, therefore, that the differences in microvascular responses between women with a normal pregnancy and those
with PE result from changes at a level further down from the
endothelium and are possibly related to a compensatory
increase in the sensitivity to nitric oxide at the smooth muscle
level.
A change in the sensitivity of the microvasculature to nitric
oxide in PE is of primary importance and is not a consequence of raised blood pressure because enhanced responses
to sodium nitroprusside were apparent at 22 weeks’ gestation,
before there were any clinical signs of PE. These findings
suggest that maternal alterations in the response to nitric
oxide might be an important factor in the subsequent development of PE. It has been reported recently that a vasoactive
circulating factor(s), capable of altering myometrial endothelial function, is present in plasma samples weeks or months
before the diagnosis of preeclampsia.5 It is possible that one
of the actions of this circulating factor(s) is to alter the
endothelial production of nitric oxide and subsequently the
actions of nitric oxide on smooth muscle.
Maternal abnormalities of endothelial function and nitric
oxide responsiveness in women with PE might increase
cardiovascular risk in later life.10 –12 However, we did not find
any postpartum differences in microvascular responses between women with normal pregnancies and PE women. One
reason for this discrepancy might be that we measured our
post partum subjects after a relatively short period (6 weeks).
The precise role of nitric oxide in PE remains unclear. The
vascular changes during normal pregnancy have been attributed, in part, to nitric oxide, although this is not a consistent
finding. Forearm vasoconstrictor responses to nitric oxide
inhibition have been shown to be reduced in normal pregnancy in 2 studies2,26 but not in the study by Bowyer et al25
The studies by Anumba et al2 and Bowyer et al25 both showed
that the effect of nitric oxide inhibition is the same on the
vessels of preeclamptic women as in normal pregnancy.
Circulating levels of nitrite are reported to be decreased in
patients with PE,27 supporting the concept that diminished
nitric oxide synthesis contributes to the pathophysiology of
PE. Other studies, however, indicate that in fact higher levels
Endothelial Dysfunction in Preeclampsia
1127
of nitric oxide are produced,28 –30 perhaps as a compensatory
mechanism to offset the impaired placental perfusion in PE.
Of interest is the recent study by Wang et al31 who reported
that endothelial nitric oxide synthase expression is decreased
in PE. This raises the question as to whether the studies
showing increased production of nitric oxide reflect increased
endothelial production or whether nitric oxide is produced
from other sources. In the present study the increased sensitivity to sodium nitroprusside might result from a compensatory response of the microvessels to decreased expression of
nitric oxide synthase.
The incidence of complications in our normal Doppler
group was higher than previously reported. However, this
study was not designed to assess the sensitivity or specificity
of Doppler waveform analysis as a screening test; this has
been addressed in previous studies and our experimental
design may have contributed to the increased incidence. We
used Doppler analyses as a method of identifying a cohort of
women at risk for pregnancy complications to facilitate
longitudinal plasma sampling. Although the presence of
bilateral notching has been shown to adversely affect endothelial function,7,32 we did not find any differences in microvascular function between women with and without notches.
The resulting sample size of women with PE was relatively
small (n⫽15), and therefore we must be cautious with
generalization of our findings. Nevertheless, we feel that the
resulting sample size is sufficient to give us a true reflection
of the vascular changes that occur during PE. Ramsay et al
used similar methodology to ours in 9 women with diabetes
and 16 control subjects and found significant differences
within each group when comparing microvascular responses
during pregnancy with those in the postnatal period.33 Additionally, we have previously shown that significant differences in microvascular responses before and after intervention are measurable using a paired comparison in 16
subjects.34
Perspectives
We have shown that skin microvascular responses are enhanced in women in whom PE develops. This enhancement in
vascular function is over and above that seen in normal
pregnancy and possibly results from a compensatory response
of the microvasculature to decreased nitric oxide production.
Importantly, these changes within the microcirculation precede the onset of clinical disease by weeks or months. Early
assessment of vascular function, in women at increased risk
for PE, might help in the identification of potentially vulnerable patients, and enable therapeutic strategies to be targeted
to this potentially dangerous condition.
Acknowledgments
This study was funded by the British Heart Foundation. J.J.F.B. and
F.K. receive funds from the Sir John Fisher Foundation. TENOVUS
Tayside provided funds for the laser Doppler imager.
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Changes in Endothelial Function Precede the Clinical Disease in Women in Whom
Preeclampsia Develops
Faisel Khan, Jill J.F. Belch, Maureen MacLeod and Gary Mires
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Hypertension. 2005;46:1123-1128; originally published online October 17, 2005;
doi: 10.1161/01.HYP.0000186328.90667.95
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