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Biol Reprod 2006, 10.1095/biolreprod.106.051607
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BIOLOGY OF REPRODUCTION 75, 518–523 (2006)
DOI: 10.1095/biolreprod.106.051607
© 2006 by the Society for the Study of Reproduction, Inc.

Research Article

Reactivity of Human Placental Chorionic Plate Vessels from Pregnancies Complicated by Intrauterine Growth Restriction (IUGR)1

Mark Wareing 2, Susan L. Greenwood , Gregor K. Fyfe , and Philip N. Baker 

Division of Human Development, Maternal and Fetal Health Research Center, The University of Manchester, St. Mary's Hospital, Manchester M13 0JH, United Kingdom

ABSTRACT

A successful pregnancy is dependent on liberal placental perfusion via the maternal and fetal circulations. Doppler waveform analyses of umbilical arteries suggest increased resistance to flow in the fetoplacental circulation of pregnancies complicated by intrauterine growth restriction (IUGR). Neither the site nor the mediators responsible for this altered vascular reactivity are known, to date. In placentas in normal pregnancy, reduced oxygenation promotes contraction of the in vitro-perfused placental cotyledon and modulates agonist-induced contraction of chorionic plate arteries and veins. Placental oxygenation has also been suggested to be reduced in IUGR. We tested the hypothesis that oxygen tension could directly modify placental chorionic plate vessel vasoreactivity in IUGR. Small arteries and veins from the chorionic plate were dissected from biopsies from placentas of pregnancies complicated by IUGR and were studied using parallel wire myography. Vasoconstriction at 20%, 7%, and 2% oxygen was assessed utilizing the thromboxane mimetic U46619. Experiments were also performed in the presence of 4-aminopyridine (4AP), a blocker of voltage-gated potassium channels. Increased oxygenation reduced venous vasoconstriction but did not modify arterial vasoconstriction. 4AP increased basal tone in arteries and veins. We suggest that venoconstriction in response to hypoxia may provide a mechanism for increased fetoplacental vascular resistance associated with IUGR.

placenta, pregnancy

INTRODUCTION

Intrauterine growth restriction (IUGR) is an important pregnancy complication. In the short term, affected fetuses are at a greater risk of neonatal complications such as stillbirth and respiratory distress [1, 2], and in the longer term, adults face increased risk of cardiovascular complications such as hypertension and diabetes [3, 4].

The etiology of IUGR is unclear, but in the absence of a fetal (e.g., genetic) or maternal (e.g., preeclampsia) pathology, reduced fetal growth can be ascribed to placental insufficiency. Abnormal uterine and umbilical artery Doppler waveforms indicate a state of increased resistance and placental hypoperfusion.

Hypoperfusion in IUGR could be a product of failed maternal spiral artery transformation and peripheral villous maldevelopment (e.g., as described by Hitschold et al. [5]). Abnormal structure of fetoplacental vessels may increase vascular resistance, as detected by atypical Doppler waveforms [6, 7]. Alternatively, vascular embolization, as induced by microsphere injection in animal models, produces abnormal Doppler indices similar to those associated with IUGR and may offer another mechanism for hypoperfusion [8–10]. However, basal perfusion pressure in perfused placental cotyledons in vitro is similar in normal and IUGR pregnancies, with abnormal Doppler waveforms and villous development [11]. This suggests that increased resistance in IUGR may not be attributed solely to fetoplacental morphological vascular abnormalities.

Constriction and relaxation of fetoplacental arteries and veins have been demonstrated in response to a number of agonists [12–15], with relaxation being elicited by increasing intraluminal flow [16]. Increased fetoplacental vascular resistance could also arise from an alteration in the balance of vasoconstrictor and vasodilatory effects (e.g., as described by Walsh [17] and by Molnar and Hertelendy [18]), via a change in the expression or response to agonists or via an alteration in the sensitivity of control mechanisms to physical factors such as tissue oxygenation.

Findings from a number of studies using the perfused placental cotyledon technique have suggested that hypoxia promotes vasoconstriction in the fetoplacental vasculature [19–22]. As in hypoxic pulmonary vasoconstriction, it has been suggested that hypoxia-induced fetoplacental vasoconstriction may be achieved via the modification of voltage-dependent potassium (KV) channel activity [22]. It has also been demonstrated that media oxygenation can modify vascular reactivity directly in fetoplacental arteries and veins [23] and that chorionic plate arteries and veins express mRNA and protein for members of the KV channel superfamily [24]. Altered placental oxygenation is a feature of IUGR [25]. This or an abnormal response of fetoplacental vessels to fluctuations in oxygenation, perhaps related to altered expression of KV channels, might underlie the increased fetoplacental vascular resistance associated with IUGR pregnancies.

Therefore, we hypothesized that in IUGR oxygen tension could directly modify placental chorionic plate vessel vasoreactivity. To test this hypothesis, we assessed 1) the vascular reactivity of chorionic plate arteries and veins from pregnancies complicated by IUGR, 2) whether vasoconstriction in IUGR was modified by alteration of media oxygenation, and 3) whether manipulation of KV channel activity may affect vasoconstriction in IUGR.

MATERIALS AND METHODS

This work was performed with the approval of the ethics committee of Central Manchester Healthcare Trust. Informed consent was obtained for all tissue used in the study.

Samples

Placentas (N = 23) were obtained following vaginal delivery or after elective Caesarean sections in women whose pregnancies were complicated by IUGR. Women were identified and recruited on the basis of reduction in fetal growth and serial antenatal ultrasound biometry predicting fetal abdominal circumference below the 10th centile for gestational age (with or without reduced amniotic fluid volume). Final inclusion was determined by postdelivery calculation of the individualized birth weight ratio (IBR) in the 5th centile or lower for gestational age. IBR relates to a predicted birth weight calculated using independent coefficients for gestation at delivery, including fetal sex, parity, ethnicity, and maternal height and booking weight. This method was chosen as it more accurately identifies pregnancies with poor outcome than alternative methods based on birth weight for gestational age alone [26]. Women with preexisting medical disorders (e.g., hypertension and diabetes) or pregnancies with identified fetal anomalies were excluded.

Myography

Small chorionic plate arteries and veins were dissected within 30 min of delivery and mounted onto 40-µm steel wires on a Danish Myotechnologies 610M wire myography (Aarhus, Denmark) as described previously [14, 15]. Vessels were bathed in 6 ml of physiologic saline solution (PSS) (119 mM NaCl, 25 mM NaHCO3, 4.69 mM KCl, 2.4 mM MgSO4, 1.6 mM CaCl2, 1.18 mM KH2PO4, 6.05 mM glucose, and 0.034 mM EDTA [pH 7.4]), warmed to 37°C, and gassed with 5% CO2 in air (BOC Gases, Worsley, U.K.). Vessel lengths (under no applied tension) were measured on completion of the mounting procedure using a calibrated eyepiece graticule.

General Chemicals

General chemicals and pharmacological agents were obtained from Sigma-Aldrich or from BDH Laboratory Supplies.

Normalization

Chorionic plate arteries and veins were normalized to 0.9 of L5.1kPa (0.9 of the vessel diameter at an intraluminal pressure of 5.1 kPa) at three different oxygen tensions as described elsewhere in detail [14, 15]. The oxygen tension was not changed during the experimental protocol. Normalization to 0.9 of L5.1kPa produced passive pressures of 2.51 ± 0.17 kPa (18.9 ± 1.3 mm Hg; n = 54 from N = 21) in arteries and 2.20 ± 0.24 kPa (16.6 ± 0.18 mm Hg; n = 41 from N = 18) in veins (i.e., similar to in vivo findings [27]). After normalization, vessels were equilibrated for 20 min before the commencement of vasoactive studies. Vessel viability was assessed using 120 mM KCl PSS (KPSS).

Effect of Oxygenation on Agonist-Induced Contraction

Experiments were performed in vessels normalized and equilibrated in three gas tensions: 5% CO2 in air (18%-20% oxygen), 5% CO2 in 5% oxygen (4.5%-5.8% oxygen), and 5% CO2 in nitrogen (0.5%-1.2% oxygen), termed the 20%, 7%, and 2% oxygen groups, respectively. Oxygenation was assessed directly in the myograph tissue baths using an oxygen meter (measurement accuracy, ±1%; WPI Inc., Sarasota, FL). Chorionic plate arterial and venous contraction was elicited using the thromboxane mimetic U46619 (10–10–2 x 10–6 M in 2-min increments/5-min plateau) [14, 15].

Effect of KV Channel Blockade on Basal Tone and U46619-Induced Contraction

Chorionic plate arteries and veins were exposed to the KV channel blocker 4-aminopyridine (4AP, 10–3 M) for 5 min and then contracted with U46619 (10–10–2 x 10–6 M). Time controls exposed to an equivalent volume of diluent were performed in parallel.

Statistical Analysis

Vessel tension production was expressed as Ki (active effective pressure) in kilopascals. Ki is calculated from {Delta}T (active wall tension in mN per millimeter) divided by the normalized internal radius (in millimeters) of the vessel. Data were tested for goodness of fit to the Gaussian distribution using the Kolmogorov-Smirnov, D'Agostino and Pearson, and Shapiro-Wilk normality tests. If the data failed any of these statistical tests, they were subsequently assessed using the relevant nonparametric statistical test. Data are expressed as mean ± SEM with n vessels from N placentas. P < 0.05 was indicative of statistical significance.

RESULTS

General Vessel Characteristics

The study utilized 23 placentas from women (median age, 29 years [range, 18–43 years]; median parity, 1 [range, 0–3]) whose pregnancies (median gestation, 38 ± 6 wk [range, 30 ± 1 to 41 ± 2 wk]) were complicated by IUGR. All pregnancies were normotensive (median systolic pressure, 110 mm Hg [range, 90–132 mm Hg]; median diastolic pressure, 66 mm Hg [range, 50–83 mm Hg]). Birth weight (median birth weight, 2340 g [range, 646-3150 g]) was used to confirm IUGR, calculated from the centile of IBR (median, 0 [range, 0–4]). Chorionic plate artery diameters were 291 ± 26 µm (n = 22, N = 7), 276 ± 23 µm (n = 16, N = 7), and 275 ± 37 µm (n = 16, N = 7) at 20%, 7%, and 2% oxygen, respectively. Chorionic plate vein diameters were 351 ± 48 µm (n = 13, N = 5), 333 ± 35 µm (n = 16, N = 7), and 360 ± 25µm (n = 12, N = 6) at 20%, 7%, and 2% oxygen, respectively.

Basal Tone in Placental Chorionic Plate Arteries and Veins

Basal tone in chorionic plate arteries was 2.7 ± 0.3 kPa (n = 22, N = 7), 1.9 ± 0.3 kPa (n = 16, N = 7), and 2.8 ± 0.3 kPa (n = 16, N = 7) at 20%, 7%, and 2% oxygen, respectively (P > 0.05, Kruskal-Wallis test). Basal tone in chorionic plate veins was 1.8 ± 0.2 kPa (n = 13, N = 5), 2.7 ± 0.5 kPa (n = 16, N = 7), and 2.2 ± 0.6 kPa (n = 12, N = 6) at 20%, 7%, and 2% oxygen, respectively (P > 0.05, Kruskal-Wallis test). 4AP, at 10–3 M, increased basal tone in chorionic plate arteries and veins (P < 0.05, Wilcoxon signed rank test) (Table 1), although this did not achieve significance in arteries at 7% oxygen and in veins at 2% oxygen (P > 0.05, Wilcoxon signed rank test). Time controls showed no alteration in basal tone (data not shown).


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  		TABLE 1. Effect of 4AP on basal tone of chorionic plate arteries and veins.a

Contraction of Placental Chorionic Plate Arteries and Veins

Addition of KPSS produced sustained arterial and venous contraction (Table 2). U46619 induced significantly greater contraction compared with smooth muscle depolarization using KPSS (P < 0.05, Wilcoxon signed rank test) except at 20% oxygen. Maximal KPSS or U46619 contractions were unaffected by oxygenation in arteries or veins (P > 0.05, Kruskal-Wallis test).


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  		TABLE 2. Contraction of chorionic plate arteries and veins.a

Dose-response curves for arteries exposed to U46619 are shown in Figure 1. Arterial contraction was not significantly altered by oxygenation (P > 0.05, two-way ANOVA). Contraction of arteries from IUGR placentas was compared with data from normal placentas [23]. In IUGR, arterial contraction was increased but only at 20% oxygen (Fig. 1B) (P < 0.05, two-way ANOVA).


Figure 1
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  		FIG. 1. U46619-induced contraction of placental chorionic plate arteries; active effective pressure production (Ki in kilopascals) vs. log concentration of U46619 (10–x M). A) Lack of effect of oxygenation on IUGR placental arterial contraction. B) Increased IUGR arterial contraction at 20% oxygen. C) IUGR arterial contraction unaffected at 7% oxygen. D) IUGR arterial contraction unaffected at 2% oxygen. Data are mean ± SEM; n vessels from N placentas. Significance at P < 0.05 was assessed using two-way ANOVA followed by Bonferroni post hoc test (*). Control data (B–D) from Wareing et al. [23] (reprinted with permission from Elsevier)

Dose-response curves for veins exposed to U46619 are shown in Figure 2. Venous contraction was significantly reduced at 20% oxygen (P < 0.05, two-way ANOVA). Contraction of veins from IUGR placentas was compared with data from normal placentas [23]. In IUGR, venous contraction was increased at 7% and 2% oxygen but not at 20% oxygen (Fig. 2, B–D) (P < 0.05, two-way ANOVA).


Figure 2
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  		FIG. 2. U46619-induced contraction of placental chorionic plate veins; active effective pressure production (Ki in kilopascals) vs. log concentration of U46619 (10–x M). A) Increased oxygenation reduces contraction of IUGR placental veins. B) IUGR venous contraction unaffected at 20% oxygen. C) Increased IUGR venous contraction at 7% oxygen. D) Increased IUGR venous contraction at 2% oxygen. Data are mean ± SEM; n vessels from N placentas. Significance at P < 0.05 was assessed using two-way ANOVA followed by Bonferroni post hoc test (*). Control data (B–D) from Wareing et al. [23] (reprinted with permission from Elsevier)

Effect of 4AP on Arterial and Venous Contraction

Preincubation with 10–3 M 4AP significantly modified the dose-response curves to U46619. Contraction was increased at all oxygen levels in arteries and veins, without an alteration in the sensitivity (EC50; the effective concentration producing 50% of the maximal response) to agonists (Fig. 3 and Table 3) (P < 0.05, repeated-measures ANOVA).


Figure 3
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  		FIG. 3. Effect of 4AP on U46619-induced contraction of placental chorionic plate arteries and veins; active effective pressure production (Ki in kilopascals) vs. log concentration of U46619 (10–x M). A–C) 4AP increases contraction of IUGR placental arteries at 20%, 7%, and 2% oxygen. D–F) 4AP increases contraction of IUGR placental veins at 20%, 7%, and 2% oxygen. Data are mean ± SEM; n vessels from N placentas. Significance at P < 0.05 assessed using repeated-measures ANOVA followed by Bonferroni post hoc test (*)


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  		TABLE 3. Effect of 4AP on U46619-induced contraction of chorionic plate arteries and veins.a

DISCUSSION

Placental chorionic plate arterial and venous contraction to a number of agonists, including the thromboxane mimetic U46619, has been demonstrated [12–15, 28–31]. It has been further shown that oxygenation can modify arterial contraction and venous relaxation in normal pregnancy [23]. Oxygenation of the placenta could be affected in IUGR [32], leading to altered perfusion or ischemia-reperfusion, which could further affect vessels downstream of the chorionic plate. In IUGR, oxygen saturation is significantly reduced (from 16 to 14 mm Hg and from 28 to 26 mm Hg in umbilical arteries and veins, respectively [25]). Similar levels of oxygen have been measured in amniotic fluid in normal pregnancy (from 16 to 24 mm Hg [33, 34]) but have yet to be determined in IUGR, to date.

Herein, we demonstrated that oxygenation did not significantly modify U46619-induced contraction of chorionic plate arteries from pregnancies complicated by IUGR. However, compared with normal pregnancy data at each oxygenation level [23], arterial contraction was increased but only in hyperoxia. This increased contractility of chorionic plate arteries from IUGR pregnancies is similar to more recent data [35] in which increased arterial contraction was found in IUGR compared with normal pregnancy (at 20% oxygen); arterial contraction was not correlated with umbilical artery Doppler indices.

Venous contraction in IUGR was decreased in hyperoxia compared with normal oxygenation; this was unlike normal pregnancy, in which oxygenation did not affect venous contractility [23]. Relative to previous data [23], venous contraction at 7% and 2% oxygen was increased compared with veins from normal pregnancy placentas. Although it could be argued that one should exercise caution when making such a direct comparison, it is important to note that identical experimental equipment and protocols were utilized in the generation of the two data sets. Therefore, our data suggest that decreased oxygenation from physiologic to pathologic levels elicits increased thromboxane-induced contractility. This is of special interest because thromboxane production is reported to be associated with IUGR placentas [36], and overexpression of thromboxane receptors is associated with an IUGR phenotype in mice [37]. The increased venous contractility we noted in normal oxygenation and hypoxia fits nicely with Doppler measurements of blood flow in the umbilical vein in IUGR, which show a fall in flow velocity but no difference in umbilical vein diameter compared with normal pregnancy [38, 39]. Therefore, this increased venous contractility may contribute to the reduced growth in IUGR by restricting the supply of nutrients and oxygen to the fetus.

KV channels affect vascular tone via their contribution to the resting membrane potential of smooth muscle cells and via their involvement in the mechanisms of action of a number of endogenous dilators and constrictors, including U46619 [40, 41]. KV channels have also been demonstrated to be important in the response of pulmonary vessels to hypoxia [42, 43], in which inhibition leads to vasoconstriction. A similar reversible inhibition of KV channels has been noted in vascular smooth muscles isolated from human placental arteries [22], suggesting that fetoplacental vessels may also show a contractile response to hypoxic episodes. The mRNA expression of KV2.1 and KV9.3 channels has been demonstrated [24], and we show herein that addition of 4AP increases basal tone and U46619-induced contraction of chorionic plate arteries and veins. Together, these data suggest that KV channels may be important in the control of tone in IUGR.

Manipulation of oxygen tension produced variable effects on the actions of 4AP. In normal pregnancy, 4AP significantly increased arterial and venous basal tone independent of oxygenation [24]. Generally, 4AP increased basal tone, although this trend did not achieve significance at 7% oxygen in arteries or at 2% oxygen in veins. Therefore, in IUGR blood vessels, KV channels appear to be important regulators of tone in the absence of agonists. In the presence of U46619-induced tone, contraction was increased in the presence of 4AP, suggesting that blockade of 4AP-sensitive KV channels promoted contraction. This effect was independent of oxygen level, and 4AP did not produce a consistent alteration in tone at comparable doses of U46619; the effects of 4AP were no greater in reduced oxygen compared with normal oxygen (Fig. 3). Although there may be a role for KV channels in the response of IUGR fetoplacental vessels to hypoxia, which can be demonstrated in isolated smooth muscle cells from normal pregnancy [22] at least with respect to IUGR, these data suggest that there must be more subtle regulation of tone in the intact vessels, perhaps via the vascular endothelium-dependent mechanisms. We also noted increased contraction of IUGR arteries at 20% oxygen and veins at 7% and 2% oxygen compared with vessels from normal pregnancy. This effect could be attributable to reduced KV channel activity, as addition of 4AP to placental arteries and veins from normal placentas produces a similar shift in U46619-induced contraction [24]. Confirmation of this assertion would require further electrophysiologic or molecular expression studies.

In summary, we have demonstrated the following: 1) In IUGR, increasing oxygen tension modifies venous but not arterial contraction to the thromboxane mimetic U46619. 2) Venous contraction is increased in IUGR compared with normal pregnancy at 7% and 2% oxygen. 3) KV channels modify basal tone and agonist-induced contraction of fetoplacental arteries and veins but are unlikely to be solely responsible for altered responses to media oxygenation.

FOOTNOTES

1 Supported by Tommy's the baby charity (Maternal and Fetal Health Research Center) and by a British Heart Foundation Intermediate Clinical Research Fellowship (M.W.; grant FS/03/051). Back

2 Correspondence: Mark Wareing, Division of Human Development, Maternal and Fetal Health Research Center, The University of Manchester, St. Mary's Hospital, Hathersage Road, Manchester M13 0JH, United Kingdom. FAX: 44 0161 276 5474; Mark.Wareing{at}manchester.ac.uk Back

Received: 9 February 2006.

First decision: 14 March 2006.

Accepted: 11 May 2006.

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