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Obstetrics & Gynecology 2005;105:626-632
© 2005 by The American College of Obstetricians and Gynecologists
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ORIGINAL RESEARCH

Abnormal Endothelium-Dependent Microvascular Reactivity in Recently Preeclamptic Women

Judith Blaauw*{ddagger}, Reindert Graaff, PhD{ddagger}, Maria G. van Pampus, MD, PhD*, Jasper J. van Doormaal, MD, PhD{dagger}, Andries J. Smit, MD, PhD{dagger}, Gerhard Rakhorst, PhD{ddagger} and Jan G. Aarnoudse, MD, PhD*

From the Departments of *Obstetrics and Gynecology, {dagger}Internal Medicine, and {ddagger}Biomedical Engineering, Groningen University Medical Centre, Groningen, The Netherlands.


   ABSTRACT
TOP
ABSTRACT
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
OBJECTIVE: To assess endothelial function at the level of skin microvasculature, using iontophoretic administration of acetylcholine (endothelium-dependent vasodilator) and sodium nitroprusside (endothelium-independent vasodilator), in women who recently had a preeclamptic pregnancy.

METHODS: Microvascular skin reactivity was assessed by laser Doppler perfusion monitoring and iontophoresis of acetylcholine (ACh) and sodium nitroprusside (SNP) in 25 women with a history of early onset preeclampsia and 23 women with previous uncomplicated pregnancies, all of whom were between 3 and 11 months postpartum.

RESULTS: Mean (± standard error of the mean) ACh-mediated vasodilatation, expressed as a percentage increase in flux, was higher in women who recently had a preeclampsia than in controls (535 ± 46% versus 314 ± 29%, P < .001). In contrast, SNP-mediated vasodilatation was not significantly different (560 ± 71% versus 483 ± 69%, P = .4) in both groups. Linear regression analysis revealed that the difference in ACh-mediated vasodilatation was explained by preeclampsia (P = .004), whereas vascular risk factors such as maternal age, diastolic blood pressure, and family history of premature cardiovascular diseases had no significant effect.

CONCLUSION: The increased ACh-mediated vasodilatation in the microcirculation of recently preeclamptic women indicates abnormal endothelial function. Furthermore, it may represent a compensatory response to an impaired vasodilatory response of the macrocirculation, thereby supporting the hypothesis of an underlying (micro)angiopathy.

LEVEL OF EVIDENCE: II-2

Preeclampsia is a serious complication of pregnancy, occurring in 4–5% of all first pregnancies, and is characterized by hypertension, proteinuria, increased peripheral resistance, and reduced organ perfusion. Generalized endothelial cell activation or dysfunction is considered to underlie many of the symptoms of preeclampsia. Abnormal placentation resulting in placental hypoperfusion with subsequent release of placental factors in the maternal circulation is thought to cause this endothelial dysfunction,1 whether or not in combination with predisposing maternal factors. Much of the evidence for this hypothesis has been based on circulating endothelial markers2,3 or on data gathered on reactivity of isolated vessels in organ chambers4 or from studies regarding behavior of large blood vessels.5,6 However, data on in vivo endothelial function in the microcirculation is scarce and inconsistent.

A recently introduced noninvasive method to assess endothelial function in the microcirculation in vivo includes the combination of laser Doppler perfusion monitoring7 and iontophoresis of vasoactive agents. This makes it possible to evaluate local vasodilator responses via endothelium-dependent and endothelium-independent pathways. With this method, increased acetylcholine-mediated (endothelium-dependent) reactions in the vessels of the forearm have been reported in preeclamptic women during pregnancy.8 However, another study using a similar technique, performed in women 15–25 years after their preeclamptic pregnancy, showed reduced endothelium-dependent vasodilator responses.9 Latent hemodynamic abnormalities have also been found in women studied at least 5 months after a preeclamptic pregnancy.10

The extensive hemodynamic adaptations during pregnancy and the by-definition different blood pressure levels in preeclampsia hamper comparison with controls or with the nonpregnant situation, while in the long term endothelial function could have been influenced by intercurrent events. Therefore, the aim of our study was to examine endothelial microvascular function at a time when the hemodynamic effects of pregnancy are no longer present, but within a reasonable time span postpartum, so as to prevent too much interference with intercurrent events.


   MATERIALS AND METHODS
TOP
ABSTRACT
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
From January 2003 to April 2004, all women who had been hospitalized in the University Hospital Groningen for severe early onset (gestational age < 34 weeks) preeclampsia were asked to participate after a detailed explanation of the study and protocol. Of a total of 28 women, 2 women did not respond to our letter and 1 woman refrained from participation because she lived at a long distance from the University Hospital Groningen. Recruitment of controls took place by inviting women with uncomplicated pregnancies and who delivered in our hospital and by placing advertisements in newspapers. All controls delivered between January 2003 and April 2004. Six controls did not deliver at our hospital but at home or at other hospitals. From these 6 women, all the relevant data regarding the course of pregnancy and pregnancy outcome were available. The study was approved by the medical ethics committee of the University Hospital Groningen, and all women gave informed consent.

The sample size of both groups was estimated by performing a power analysis, based on a study using the same technique, performed in healthy and preeclamptic pregnant women.8 The median ratio of the reactivity in the healthy pregnant women was 11.7. To detect a difference of 30% in microvascular reactivity with a standard deviation of 3.9 on the basis of 80% power with significance set at the 5% level, we planned to study 23 women in each group. All women had singleton pregnancies and were tested between 3 and 11 months postpartum. Preeclampsia was defined according to the criteria of the International Society for the Study of Hypertension in Pregnancy: the appearance of a diastolic blood pressure of 90 mm Hg or greater, measured at 2 occasions at least 4 hours apart, in combination with proteinuria (≥ 300 mg/24 h or 2+ dipstick) developing after a gestational age of 20 weeks in a previously normotensive woman. Hemolysis, elevated liver enzymes, and low platelet count (HELLP) syndrome was defined as serum lactate dehydrogenase more than 600 U/L, serum aspartate aminotransferase and serum alanine aminotransferase more than 50 U/L, and a platelet count less than 100 x 109/L. Severe preeclampsia was defined as previously described.11Women with pre-existing hypertension (BP before 20 weeks of gestation ≥ 140/90 mm Hg or using antihypertensive medication), diabetes mellitus, renal disease, or preeclampsia in a previous pregnancy or who were using vasoactive drugs were excluded. Small for gestational age (SGA) was defined as birth weight below the 10th percentile for fetal sex and gestational age. None of the participants used any medication during the studies.

Information on personal history, including past history of hypertension, diabetes, renal diseases, smoking habits, drug therapy, weight, length, and family history (first degree) relating to premature (in men < 55 years, in women < 65 years) cardiovascular diseases was obtained by means of a questionnaire. Sitting blood pressure was measured by a mercury sphygmomanometer (Korotkov V) at the end of the examination.

Skin perfusion was measured by a Periflux 4000 laser Doppler system in combination with a Periflux tissue heater set to 31°C (PF4005, Peritemp; all equipment from Perimed, Stockholm, Sweden). Laser Doppler perfusion monitoring is a noninvasive method to measure skin perfusion. A laser beam (wavelength of 780 nm) is conducted through optical fibers to illuminate the skin. Part of this light is backscattered by moving (red) blood cells and undergoes a frequency shift proportional to the velocity and number of moving objects. Because the precise investigated volume is unknown, the signal collected by the returning fiber is expressed in arbitrary units and referred to as flux (PU). The vascular measurements were performed between 8:00 and 12:00 am after 10 minutes of acclimatization with each subject in a sitting position, her forearm on a soft pillow at heart level in a temperature-controlled room (T = 23.4 ± 0.5°C). Tissue temperature was recorded during the measurements. Caffeine-containing drinks or smoking were not allowed 2 hours before the test.

A special iontophoresis probe (PF481-2, Perimed) containing a thermostatic probe holder was placed on the dorsal side of the middle phalanx of the third finger. A battery-powered iontophoresis controller (PeriIont 382, Perimed) was used to provide a direct current for drug iontophoresis. Iontophoresis allows charged substances to cross the skin by means of a small electrical current. Iontophoresis is based on the principle that a charged molecule migrates under the influence of an applied electrical field toward an electrode of opposite charge. Iontophoresis of acetylcholine (ACh) induces vascular smooth muscle relaxation indirectly via endothelium-derived relaxing factor(s), whereas sodium nitroprusside (SNP), a nitric oxide (NO) donor, evokes vasodilatation by directly increasing cyclic guanosine monophosphate (cGMP) in vascular smooth muscle cells.12

After a baseline recording of 10 minutes at rest (baseline flux), iontophoresis was started by setting time and current strength based on previously documented and accepted protocols of multiple fixed doses. Acetylcholine (1%, Miochol, IOLAB, Bournonville Pharma, the Hague, the Netherlands) was delivered in 7 doses of 0.1 milliamps (mA) using an anodal current for 20 seconds, with a 60-second interval between each dose to achieve a plateau phase, whereas SNP (0.1%, dissolved in NaCL 0.9%) was delivered in 9 doses of 0.2 mA using a cathodal current for 20 seconds with a 90-second interval between each dose. Acetylcholine response was measured at the dorsal side on the middle phalanx of the third finger of the dominant hand; SNP was measured on the same spot on the nondominant hand. Ten minutes after the final iontophoretic delivery, an arterial occlusion at the upper arm was performed by inflating a blood cuff more than 30 mm Hg suprasystolic for 3 minutes to determine the biological zero flux level. This is defined as the nonzero laser Doppler signal obtained from a tissue in the absence of vascular flow.15 The measurements were performed sequentially; approximately 10 minutes elapsed between the 2 measurements. The order of ACh and SNP delivery was randomized by starting the experiment with the dominant hand on even days of the week and with the nondominant hand on odd days of the week.

Vascular data are corrected by subtracting the biological zero flux from the raw data and expressed as mean (± standard error of the mean) unless stated otherwise. The mean flux of the first 10 minutes of the experiment, excluding movement artifacts, made up the baseline flux. The plateau flux was defined as the mean flux during the last 2 minutes of the plateau phase. Absolute increase was defined as the difference between plateau flux and baseline flux. Vasodilatation was calculated as the ratio of absolute increase and the baseline flux. A representative recording of flux changes during iontophoresis of ACh and arterial occlusion is shown in Figure 1.



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  		Fig. 1. Vasodilator response to iontophoretic administration of acetylcholine in an individual subject who had a preeclamptic pregnancy. Iontophoretic currents are applied each 60 seconds, starting at t = 600 seconds, resulting in an increase in flux until a plateau phase is reached. Arterial occlusion started at t = 1,560 seconds.

Blaauw. Microvascular Reactivity in Recent Preeclampsia. Obstet Gynecol 2005.

 

We used the Kolmogorov-Smirnov test to assess the normality of the data. Group differences were tested using the unpaired Student t test. When data were not normally distributed, the nonparametric Mann-Whitney test was applied. Frequencies or categorical variables were compared with the {chi}2 test. Contribution of possible confounding variables to the association of having a preeclamptic pregnancy with ACh-mediated vasodilatation was examined by linear regression analysis. Statistical analysis were performed using SPSS 11.0.1 (SPSS Inc, Chicago, IL). P = .05 was considered significant.


   RESULTS
TOP
ABSTRACT
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
A total of 48 white women participated in this study: 25 women with a history of early-onset preeclampsia and 23 healthy women with uncomplicated pregnancies. Thirteen of the 25 women in the preeclampsia group had met the criteria for the HELLP-syndrome during their pregnancy. Twelve women in the preeclampsia group and 16 controls used oral contraceptives (OC). Five women in the control group were still breastfeeding. Clinical characteristics of the study subjects are presented in Table 1. Women were similar with respect to current smoking habits and interval from delivery to day of study. Although the women who had preeclampsia had higher prevalence of family history of cardiovascular disease, it did not reach significance. In comparison with the controls, women who recently had a preeclamptic pregnancy were younger, had higher systolic and diastolic blood pressures, and had a higher body mass index. The high number of birth weights below the 10th percentile, together with the low gestational age at delivery in the group of recently preeclamptic women, underline the severity of their previous preeclamptic condition.


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  		Table 1. Clinical Characteristics of Recently Preeclamptic Women and Control Group

 

The vasodilator responses to ACh were higher in the recently preeclamptic group than the control group. On average, the percentage increase from the baseline flux was 1.7 times higher than in the control group (P = .001). The SNP responses were not different between the 2 groups. There were no significant differences between the groups in baseline flux or plateau flux. The results are presented in Table 2 and Figures 2 and 3.


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  		Table 2. Results of Microvascular Measurements

 


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  		Fig. 2. Acetylcholine-mediated vasodilatation in recently preeclamptic women and controls. Mean vasodilatation in recently preeclamptic women and controls (535 ± 46% versus 314 ± 29%, P < .001) is indicated by the horizontal lines. ACh, acetylcholine.

Blaauw. Microvascular Reactivity in Recent Preeclampsia. Obstet Gynecol 2005.

 



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  		Fig. 3. Sodium nitroprusside–mediated vasodilatation in recently preeclamptic women and controls. Mean vasodilatation in recently preeclamptic women and controls (560 ± 71% versus 483 ± 69%, P = .4) is indicated by the horizontal lines. SNP, sodium nitroprusside.

Blaauw. Microvascular Reactivity in Recent Preeclampsia. Obstet Gynecol 2005.

 
To estimate which variables were significantly associated with ACh-mediated vasodilatation, we conducted a linear regression analysis with ACh-mediated vasodilatation as the dependent variable and maternal age, diastolic blood pressure, lactation, family history of premature cardiovascular disease, and preeclampsia as independent variables. This analysis showed that preeclampsia was the only significant contributor for the observed increase in ACh-mediated vasodilatation (P = .004).


   DISCUSSION
TOP
ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Endothelium activation or dysfunction is considered to play an important role in the clinical manifestations and pathophysiology of preeclampsia.16 We studied vascular responses of the cutaneous microcirculation by means of a combination of laser Doppler perfusion monitoring and iontophoresis of ACh and SNP, provoking endothelium-dependent and endothelium-independent vasodilatation in women who recently had preeclampsia and women with uncomplicated pregnancies, 3–11 months postpartum. We found that the endothelium-dependent microvascular response to ACh was increased in women with a recent history of a preeclampsia, indicating abnormal endothelial function.

Laser Doppler perfusion monitoring is a noninvasive, suitable method for measuring skin perfusion in a semiquantitative way. The combination of laser Doppler perfusion monitoring and iontophoresis makes it possible to assess changes in the cutaneous microcirculation after administration of vasoactive drugs without systemic effects. Iontophoresis of SNP, thereby donating NO directly, is commonly believed to provoke endothelium-independent vasodilatation. The exact mechanism of ACh-mediated vasodilatation in the microcirculation has not been fully clarified. When applied to blood vessels, ACh binds to muscarinic receptors on the surface of endothelial cells, thereby activating specific G proteins inducing synthesis of NO from l-arginine. Nitric oxide acts as local messenger via an increased production of cGMP leading to smooth muscle cell relaxation.17 However, more factors, such as the vasodilator prostacyclin and the endothelium-derived hyperpolarizing factor, are released by the endothelium in response to ACh. The relative contribution of these 3 factors to the cutaneous vasodilatation remains unresolved. Whereas some authors report that it is mainly mediated by a prostanoid-dependent mechanism,18,19 others suggest the contrary.20,21 After all, vasodilatation elicited by ACh depends on an intact endothelium and is therefore commonly used to test endothelial function.

The methodology using iontophoresis and laser Doppler flowmetry has been widely used to investigate microvascular function in various vascular disease states, most commonly in diabetes mellitus. The present data are quite remarkable because endothelium dysfunction in the dermal microcirculation is usually demonstrated by reduced responses.12,22–25 Moreover, obesity and hypertension are per se associated with decreased endothelium-dependent microvascular reactivity.14,26

How do we explain the increased vasodilatory response that we found in the women who recently experienced preeclampsia? Although blood pressure levels and body mass index are higher in the group of recently preeclamptic women, these vascular risk factors did not influence the results of the ACh-mediated vasodilatation, as demonstrated in the multivariate analysis.

The higher response of skin blood flow to endothelium-dependent stimuli could potentially be explained by a baseline vasoconstrictive state caused by possible sympathetic overactivity.27 Baseline flux was somewhat higher in the control group, but the difference with the preeclampsia group was not significant. The higher mean baseline flux was the result of unexplained high baseline values of 2 women in the control group. After exclusion of these outliers, the results did not essentially change, and therefore we included these measurements. Moreover, although the increased ACh-mediated reactivity might indicate a basal vasoconstriction, only a slight trend (P = .4) is seen in the SNP-mediated reactivity, and therefore this argument cannot be established.

Another explanation could be that the previously preeclamptic condition has differentially affected the penetration of ACh through the skin. Although we cannot totally reject this possibility, it seems very unlikely because the number of delivered doses of both ACh and SNP resulted in maximal responses in healthy controls.

Few studies have been performed with this technique during or after a preeclamptic pregnancy. During preeclampsia, Eneroth-Grimfors et al28 did not find any difference in reaction on ACh, but they used only one charge stimulus and could possibly, therefore, not reach a plateau level. However, Davis et al8 found increased ACh-mediated responses during preeclampsia, a finding similar to the response in our postpartum group. More recently, a study performed in women who had a preeclamptic pregnancy 15–25 years ago demonstrated impaired responses for both ACh and SNP, indicating a vascular dysfunction farther downstream at the level of vascular smooth muscle cells.9 In all these studies, measurements were done on the forearm, a relatively low-flow area, whereas we performed our studies on the fingers, a relatively high-flow area. To test whether the location of the measurement could have influenced our data, we measured the microvascular reactivity on ACh and SNP in some participants, not only on the fingers, but also on the forearm. Because our results of the reactivity on the forearm show the same trend as on the finger, we can conclude that this probably has not biased our results. Furthermore, we examined microvascular function in a situation outside (preeclamptic) pregnancy when blood pressure levels, hemodynamic alterations, and other specific preeclamptic factors had returned to prepregnancy levels, and when, on the other hand, no other confounding factors in the long term might influence our results.

Clinical consequences of endothelial dysfunction can vary depending on the vascular bed, and therefore it must be emphasized that our observation of abnormal endothelium-dependent reactivity in the skin microcirculation cannot be extrapolated to large-resistance vessels of the human body. Chambers et al5 tested vascular reactivity in the macrocirculation of preeclamptic women at a median of 3 years postpartum. They examined in a large resistance vessel (brachial artery) the reactive hyperemia following the release of a transient suprasystolic arterial occlusion and demonstrated an impaired (mainly endothelium-dependent) reactivity in women with previous preeclampsia. This observation, combined with our data, fits into a model of a hemodynamic hypothesis of the pathogenesis of angiopathy in preeclampsia, in which inability of the large vessels to vasodilate is compensated by increased reactivity of the small vessels.

In conclusion, this study demonstrates abnormal endothelial function in the skin microcirculation of preeclamptic women, 3–11 months postpartum. This abnormal endothelium-dependent response is not explained by differences in other vascular risk factors such as blood pressure, maternal age, and family history of premature cardiovascular diseases. Furthermore, we assume that the increased reactivity of the microcirculation is a compensatory response to an impaired reactivity of the macrocirculation, thereby supporting the hypothesis of an underlying (micro)angiopathy.


   Footnotes
 
Address reprint requests to: Jan G. Aarnoudse, MD, PhD, Professor of Obstetrics and Maternal Fetal Medicine, Department of Obstetrics and Gynaecology, Groningen University Medical Centre, Postbox 30.001, 9700 RB Groningen, The Netherlands; e-mail: j.g.aarnoudse{at}og.azg.nl.

Received July 27, 2004. Received in revised form October 19, 2004. Accepted December 2, 2004.

doi:10.1097/01.AOG.0000153490.41973.e0


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ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
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4. Cockell AP, Poston L. Flow-mediated vasodilatation is enhanced in normal pregnancy but reduced in preeclampsia. Hypertension 1997;30:247–51.[Abstract/Free Full Text]

5. Chambers JC, Fusi L, Malik IS, Haskard DO, de Swiet M, Kooner JS. Association of maternal endothelial dysfunction with preeclampsia. JAMA 2001;285:1607–12.[Abstract/Free Full Text]

6. Savvidou MD, Hingorani AD, Tsikas D, Frolich JC, Vallance P, Nicolaides KH. Endothelial dysfunction and raised plasma concentrations of asymmetric dimethylarginine in pregnant women who subsequently develop pre-eclampsia. Lancet 2003;361:1511–7.[Medline]

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