Published online before print January 23, 2006, doi: 10.1161/01.HYP.0000201444.80784.59
(Hypertension. 2006;47:454.)
© 2006 American Heart Association, Inc.
Original Articles |
Moderate Ascorbate Deficiency Increases Myogenic Tone of Arteries From Pregnant but Not Virgin Ascorbate–Dependent Rats
From the Magee-Women Research Institute (R.J.J.R., C.A.H., J.N., J.R.D., V.E.K., R.E.G.), Department of Obstetrics, Gynecology, and Reproductive Sciences (R.J.J.R., C.A.H., J.N.,), and Department of Environmental and Occupational Health C.A.H., V.E.K., R.E.G.), University of Pittsburgh, Pittsburgh, Pa.
Correspondence to Robin E. Gandley, Magee-Women Research Institute, 204 Craft Ave, Pittsburgh, PA 15213. E-mail rsireg{at}mwri.magee.edu
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Abstract |
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Plasma ascorbic acid is decreased in women with the pregnancy disorder preeclampsia. We used a mutant strain of rats (Osteogenic Disorder Shionogi), dependent on dietary sources of vitamin C, to investigate whether reduced intake of the vitamin would differentially affect vascular function in late-pregnant (day 19) and age-matched virgin rats. The animals were given either 1 mg/mL of ascorbic acid ad libitum in drinking water [fully supplemented (FS)] or 0.25 mg/mL [marginally supplemented (MS)]. Fetal weights were 21% lower in MS than FS rats, whereas mean maternal weights and pup numbers did not differ. Small mesenteric arteries (diameter, 268±7 µm) were mounted in a pressurized arteriograph. Myogenic reactivity (contractile response to step increases in intraluminal pressure) was increased in arteries from MS pregnant compared with FS pregnant rats to levels observed in virgin rats. Ascorbic acid intake did not affect myogenic responses of arteries from virgin rats. Hence, the normal pregnancy-induced reduction in myogenic reactivity was abrogated in MS pregnant animals. Inhibition of nitric oxide synthase had no effect on the myogenicity of arteries from virgin or MS pregnant rats but increased myogenicity of FS pregnant rats to the level of MS pregnant rats. Free radical scavengers reversed the accentuated myogenicity of MS pregnant rats without affecting FS pregnant or virgin rat arteries. These data indicate that moderate ascorbate deprivation increases mesenteric artery myogenic responsiveness during pregnancy. This increase may result from a decrease in nitric oxide–mediated modulation of the myogenic contractile response.
Key Words: pregnancy • preeclampsia • rats • vessels • antioxidants
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Introduction |
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Normal pregnancy is accompanied by profound cardiovascular changes including alterations in endothelial cells that contribute to increased vasodilation, reduced constriction, and reduced contractility of systemic resistance arteries. These normal adaptive changes are attenuated in women with preeclampsia, a human specific hypertensive disorder that is a leading cause of maternal and fetal mortality, fetal growth restriction, and premature delivery.1 Endothelial dysfunction/damage is thought to account for many of the complex manifestations of preeclampsia, including vasospasm and multiorgan ischemic damage. Several lines of evidence suggest that oxidative stress, including oxidative destruction of NO, and inflammation contribute to maternal vascular dysfunction in preeclampsia.2–5
Maternal plasma concentrations of the antioxidant nutrient vitamin C (ascorbate) are decreased by 20% to 50% in women with preeclampsia compared with women with normal pregnancy.2,6–8 These decreases are manifested as early as weeks 20 in gestation in women who subsequently develop preeclampsia and, thus, are unlikely to be a consequence of the disease.6 Ascorbate oxidation is increased in maternal blood from women with preeclampsia.8,9 Dietary deficiency might be an additional reason for low ascorbate.10 A recent randomized, controlled trial of women at high risk of preeclampsia showed that daily oral administration of vitamins C and E beginning at week 22 of gestation was associated with a significant decrease in the incidence of preeclampsia and improvement in biochemical indices relating to oxidative stress, endothelial function, and placental function.11,12
Using pressurized arteriographs to study the behavior of small-diameter mesenteric arteries in vitro, previous studies have shown that the vascular adaptation to pregnancy in the rat appropriately models the human in many respects. This includes decreases in intrinsic myogenic reactivity and increased responsiveness to endothelium-mediated vasodilators.13,14 We hypothesized that endothelium-dependent vasodilator responses of isolated mesenteric arteries would be impaired in female rats subjected to moderate ascorbate deprivation in a manner accentuated by pregnancy and reversible by pretreatment of the arteries with free radical scavengers. To test this hypothesis, we used a strain of rats [Osteogenic Disorder Shionogi (ODS)] unable to synthesize ascorbate because of a lack of L-gulonolactone oxidase.15 We chose this model, because the latent ascorbate deficiency sometimes observed in humans might not be adequately replicated in most animals (including wild-type rats) because of the ability of these animals to synthesize ascorbate. Humans and primates lack L-gulonolactone oxidase, rendering them incapable of synthesizing ascorbate and, thus, completely dependent on dietary sources of the vitamin. We adjusted dietary intake of ascorbate in this rat model such that plasma ascorbate concentrations were lowered to the approximate degree observed in women with preeclampsia, without inducing scorbutic changes, in both the pregnant or nonpregnant state. We measured active and passive mechanical properties of arteries, fetal weights, litter size at term, plasma concentrations of malondialdehyde (MDA; a marker of oxidative stress), cholesterol, triglycerides, and free fatty acids.
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Methods |
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Animal Model
Animals used in this study were derived from a colony of ODS rats (CLEA Japan Inc). All of the rats were fed a standard rat chow (60.0% of total energy as carbohydrate; Laboratory Diet), which is devoid of ascorbic acid. The breeding colony received ascorbic acid (1 mg/mL) in their drinking water ad libitum. Twelve- to 14-week-old virgin female rats were bred. On day 0 of gestation, the animals were either continued on the ascorbic acid supplementation administered since birth [fully supplemented (FS)], or they were given one-quarter of this concentration [marginally supplemented (MS); 0.25 mg/mL given ad libitum in drinking water]. Age-matched virgin rats were also assigned to either FS or MS groups and received the corresponding amounts of ascorbic acid in their drinking water for 20 days.
All of the animals were euthanized by intraperitoneal injection of sodium pentobarbital (0.1 mg/kg body weight), and blood was collected by cardiac puncture. Serum and plasma were stored at –70°C. For vitamin C measurement, heparinized plasma was acidified on ice and in the dark with an equal volume of 10%(v/v) metaphosphoric acid.
A section of the mesenteric arcade, 5 to 10 cm distal to the pylorus, was rapidly removed and placed in ice-cold HEPES-buffered (pH 7.4) physiological saline solution (HPSS). Second-order resistance arteries were prepared as described previously.16,17 The arterial segments were mounted on 2 microcannulae suspended in a dual chamber isobaric arteriograph (Living Systems) in the absence of flow. Additional description of this system is reported elsewhere.18 Transmural pressure was adjusted to 60 mm Hg, and the HPSS in the bath and lumen was maintained at 37°C and pH of 7.4 with HPSS changes every 30 minutes throughout the experiment. Arteries were equilibrated and a conditioning stretch was preformed before beginning the experiment. At the end of the experiment, arteries were treated with papaverine in a calcium-free (EDTA) buffer to inactivate vascular smooth muscle.16
Myogenic Tone Assessment
Before initiating changes in intraluminal pressure for myogenic measurements, each artery was submaximally contracted to 75% to 80% of its initial diameter with the 
-adrenergic agonist phenylephrine (PE). The dose of PE needed to achieve this constriction did not differ significantly between groups. After stable tone was initiated, pressure was lowered to 20 mm Hg for 10 minutes then increased to 120 mm Hg in 20-mm Hg–step increments. A diameter measurement was taken 5 minutes after each pressure step or after maximal response to each pressure step was achieved. Arteries were washed, equilibrated, and then treated with the NO synthase (NOS) competitive inhibitor NG-methyl-L-arginine (0.1 mmol/L), the superoxide scavenger Tiron (0.1 mmol/L), or the antioxidant N-acetyl cysteine (20.0 mmol/L) for an additional 15 minutes. The pressure step protocol was then repeated.
Responses to changes in intraluminal pressure were normalized as a percentage of the initial diameter at 20 mm Hg using the following equation: percentage change from starting diameter at 20 mm Hg= [(DX–D20)/ D20]x100. DX is the diameter at a given pressure step, and D20 is the diameter at 20 mm Hg. By convention, a positive percentage change in diameter is indicative of dilation, whereas a negative percentage change denotes arterial constriction. Therefore, an artery with increased myogenicity displays a smaller positive percentage change in diameter or a greater negative percentage change in diameter relative to control.
Agonist Concentration–Response
A separate set of arteries was exposed to cumulative concentrations of PE (0.10 to 10.0 µmol/L). The arteries were then preconstricted with PE to 50% of initial diameter and exposed to cumulative concentrations of the endothelium-dependent vasodilator methacholine (ME; 5 nmol/L to 10 µmol/L).
Passive Mechanics
Passive mechanical properties (distensibility and stress-strain relationships) of the arterial were then determined as described previously in a smooth muscle–inactivating buffer.16
Plasma and Sera Analyses
Serum total cholesterol, triglyceride, and free fatty acid concentrations were determined by enzymatic colorimetric methods. Plasma ascorbic acid measurements were made by high-pressure liquid chromatography with ultraviolet detection. Plasma MDA concentrations were also determined by high-performance liquid chromatography with ultraviolet detection.19
Superoxide Levels in Aorta
Lucigenin-enhanced chemiluminescence was used to measure superoxide in 5-mm–length rat aorta segments in a FB14 luminometer (Zylux). The data were assessed as the superoxide level measured in the aorta before and after inhibition of superoxide dismutase. Treatment with tiron confirmed the specificity of the assay for superoxide.
Statistical Analyses
Artery responses were compared using 2-way repeated measures ANOVA with post-hoc Bonferroni’s test. Mean litter sizes, fetal weights, serum lipids, and plasma MDA were all compared by ANOVA with post hoc Bonferrroni’s test. Data are given as mean±SEM. Statistical significance was accepted at a P value of <0.05.
Detailed methods are available in an online supplement at http://www.hypertensionaha.org.
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Results |
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Plasma ascorbate concentrations were reduced by &25% in MS pregnant compared with FS pregnant rats (13.8±0.9 µmol/L versus 18.1±0.9 µmol/L; P<0.05) and by 50% in MS virgin compared with FS virgin rats (12.6±3.0 µmol/L versus 26.2±7.0 µmol/L; P<0.05; Table). Plasma ascorbic acid concentrations in MS virgin and MS pregnant animals did not differ. Plasma ascorbate concentrations were lower in FS pregnant compared with FS virgin rats, although this did not achieve statistical significance.
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Fetuses from MS pregnant rats weighed significantly (21%) less on average than fetuses from FS pregnant animals (Table 1), indicative of growth restriction. There was no difference in mean litter size (number of viable pups) between MS and FS pregnant groups, indicating that fetal survival was not compromised by ascorbate restriction during pregnancy. Ascorbic acid intake had no effect on maternal weight or gestational weight gain (Table 1). As in the pregnant animals, there was no effect of ascorbate supplementation on body weight in virgin rats.
Plasma concentrations of the oxidative stress marker MDA were significantly increased in the both the virgin and pregnant MS compared with FS animals (Table 1). MDA levels were significantly higher in virgin rats compared with pregnant rats. Serum triglycerides and free fatty acids were significantly increased in pregnant compared with virgin animals irrespective of diet (Table 1). Cholesterol was also increased with pregnancy, albeit not significantly, but did not differ by ascorbate supplementation. However, serum-free fatty acids were slightly but significantly decreased in MS virgin compared with FS virgin controls (0.2±0.03 mmol/L versus 0.36±0.08 mmol/L; P<0.05).
Myogenic Response
Consistent with previous comparisons of small resistance-sized arteries from pregnant and virgin wild-type rats,13,17,20 mesenteric arteries taken from FS ODS rats at 19 days of gestation displayed a significant decrease in myogenic responsiveness (active response of arteries to rapid increases in intraluminal pressure) compared with FS virgin controls (Figure 1, P<0.0001). In marked contrast to FS pregnant rats, however, arteries from MS pregnant rats responded to pressure increases with substantial myogenic constriction (P<0.0001; Figure 1). Thus, the myogenic profile of arteries from MS pregnant rats was not significantly different than MS or FS virgin controls (Figure 1). Arteries from virgin rats displayed robust myogenic responses irrespective of diet (Figure 1). Therefore, the reduction in myogenic reactivity that normally occurs with pregnancy was absent in arteries from MS pregnant rats.
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) or MS pregnant (0.25 mg/mL in drinking water, 
; P<0.001, ANOVA; *P<0.05 by Bonferroni post hoc test FS virgin versus FS pregnant +P<0.05 FS pregnant versus MS pregnant). (b) Response of arteries from MS pregnant (
) rats were not significantly different. Data are represented as mean±SE. *P<0.05 by post hoc analysis and ANOVA.Pretreatment of arteries with the NOS inhibitor NG-methyl-L-arginine (0.1 mmol/L) resulted in a significant increase in myogenic responsiveness of arteries from FS pregnant animals (Figure 2a; P<0.05) but had no effect on the myogenic responsiveness of arteries from MS pregnant animals (Figure 2b; P=0.22). This is consistent with previous work demonstrating a role for NO in the reduced myogenic response during pregnancy.13,17,20 In contrast, pretreatment with the NOS inhibitor did not alter myogenic responses of arteries from FS or MS virgin animals (data not shown).
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We used the superoxide scavenger Tiron (0.1 mmol/L; Figure 3a and 3b) and the nonspecific free radical scavenger N-acetylcysteine (20 mmol/L; Figure 4a and 4b) to examine the impact of reactive oxygen species on the accentuated myogenic response of a separate series of artery segments from the FS and MS pregnant rats. Pretreatment with Tiron reversed the increased myogenic responsiveness of arteries from MS pregnant rats. For example, at 120 mm Hg, the change in arterial diameter expressed as a percentage of the 20 mm Hg baseline increased from –11.7% (±2.2%) before Tiron to 25.7% (±5.5%) after Tiron (Figure 3b; P<0.05), indicative of dilation. Similar effects were seen after arteries from MS pregnant rats were incubated in N-acetylcysteine; the response to this agent at 120 mm Hg expressed as a percentage of the 20 mm Hg baseline was a relative diameter increase from 1.38% (±7.2%) to 49.06% (±12.7%; Figure 4b; P<0.05). In marked contrast, neither Tiron nor N-acetylcysteine significantly altered the myogenic response of arteries from FS pregnant rats (Figures 3a and 4
a) or any virgin arteries.
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) and without (•) Tiron. Differences were not significant. (b) Arterial responses from MS (0.25 mg/mL ascorbic acid) pregnant rats after incubation with (
) and without (
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) and without (•) NAC. These differences were not significant. (b) Arterial responses from MS (0.25 mg/mL ascorbic acid) pregnant rats after incubation with (
) and without (Superoxide levels were more than double in isolated aortas from the MS group 3405±333 versus 1452±204 relative light units (RLU)/min per milligram compared with aortas from FS animals (P<0.001). Inhibition of superoxide dismutase with diethyldithiocarbamate significantly increased the level of superoxide measured in aortas from MS pregnant and virgin rats, as well as from FS pregnant rats (Figure 5). The difference in RLU/min per milligram measured before and after superoxide dismutase inhibition was significantly greater in the MS pregnant versus FS pregnant (4214±460 versus 1912±369 RLU/min per milligram; P<0.001) and MS virgin versus FS virgin (2758±189 versus 1106±149 RLU/min per milligram; P=0.002) rats.
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). SOD inhibition significantly increased superoxide levels over initial in all groups except the FS virgin aortas (*P
0.022). Superoxide levels were greater in the MS compared with the FS for both the aortas from the virgin and pregnant rats (P
Responses to Phenylephrine
There was no significant difference in the amount of initial arterial tone (initial diameter versus passive diameter of arteries at 60 mm Hg) in any of the groups examined (P=0.79). The mean amount of tone in all of the groups was 2.3±0.5% (group means, 1.7 to 2.9% tone). Contractile responses to PE were not different between FS and MS pregnant groups (data not shown). There was no significant difference in the mean concentrations of PE required to achieve a constriction equal to 50% of the maximum (mean log EC50: FS pregnant 1.14±0.05 µmol/L versus MS pregnant 0.85±0.09 µmol/L; P=0.13). Similarly, the mean log EC50 concentration for FS virgin animals (0.912±0.11 µmol/L) was not different (P=0.23) from MS pregnant animals (0.741±0.07 µmol/L; data not shown).
Responses to ME
Arteries from FS and MS pregnant rats exhibited no difference in endothelium-dependent relaxation in response to ME, with no difference in EC50 (mean log EC50 ME concentration: FS pregnant, 0.58±0.07 µmol/L compared with MS pregnant, 0.43±0.05 µmol/L; P=0.5) and with relaxations at the highest doses completely reversing PE-induced preconstriction in both groups. Likewise, there was no difference in ME concentration–response between the 2 groups of virgin rats (mean log EC50 concentrations: 0.004±0.014 µmol/L and 0.006±0.08 µmol/L for FS and MS rat, respectively; P=0.17). Arterial responsiveness to ME was increased in FS pregnant animals compared with FS virgin animals overall (P<0.05), consistent with previous data showing increased responsiveness to endothelium-dependent vasodilators in isolated arteries from gravid animals.
Passive Vessel Mechanics
There was no significant difference in arterial diameters at 100 mm Hg between groups, the overall average diameter being 268±7 µm. The slope of the change in diameter relative to the diameter at 10 mm Hg over the low strain pressure range (10 to 80 mm Hg) was used to compare distensibility.16 There was no significant difference in the slopes of the virgin FS versus MS (1.67±0.25 versus 1.46±0.19) or the pregnant FS versus MS (1.61±0.12 versus 1.56±0.10). The r2 for the distensibility curves were >0.96. The average stress–strain curves for each group were curve fit to the exponential equation, and the rate constants were compared between groups. The rate constants for the virgin FS versus MS (3.45±0.26 versus 3.97±0.39) and pregnant FS versus MS (3.94±0.25 versus 4.17±0.18) were not significantly different (P=0.21).
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Discussion |
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The aim of this study was to determine the effect of a nonscorbutic reduction of dietary ascorbate during pregnancy on vascular function and to begin to elucidate the mechanisms responsible for changes in vascular function. Using a strain of rats (ODS) that, like humans, are unable to synthesize ascorbate from glucose,15 we found that a reduction of plasma ascorbate concentrations, similar to that observed in groups of women with preeclampsia relative to normal pregnancy, is associated with a pronounced increase in myogenic reactivity of small mesenteric arteries from day 19 pregnant but not nonpregnant rats. In essence, the reduction in arterial myogenic reactivity normally associated with pregnancy was not evident (reverted to the nonpregnancy phenotype) in pregnant rats subjected to latent/marginal ascorbate deficiency. In addition to altered vascular function, fetal weights were dramatically reduced, whereas maternal body weight, maternal weight gain, and maternal behavior and appearance were not different.
Plasma ascorbate concentrations decrease with advancing gestation in the human21; in a similar fashion, we found ascorbate concentrations to be slightly (albeit nonsignificantly) lower in pregnant than nonpregnant ODS FS rats. Plasma ascorbate concentrations were significantly reduced in virgin and pregnant rats under ascorbate MS. The reduction in plasma ascorbate was more pronounced in MS virgin than MS pregnant groups; ascorbate concentrations in pregnant MS and virgin MS were roughly equivalent as a result.
Myogenic reactivity is an integrative process that depends on the endothelium, vascular smooth muscle, and extracellular matrix.13,16,22,23 Artery wall composition,16 vascular wall tension,24 and many vasoactive pathways25,26 influence the degree of myogenic reactivity. Consistent with data from normal rats,13,17,20 mesenteric arteries from FS (ascorbate-replete) ODS rats at 19 days of gestation displayed a significant decrease in myogenic responsiveness compared with FS virgin ODS controls in a manner largely reversed by the inhibition of NOS. Reduced ascorbate intake was associated with a dramatic increase in myogenic reactivity of mesenteric arteries from pregnant but not nonpregnant rats. Pretreatment of arteries with an NOS inhibitor did not additionally increase the already increased myogenic responsiveness of arteries from MS pregnant rats. Therefore, this pregnancy-specific vascular sensitivity to dietary ascorbate may result from a loss of NO-mediated modulation of the myogenic contractile response. Pregnancy appears to confer a unique sensitivity of the vascular endothelium to several potentially adverse agents, including homocysteine,27 ethanol,28 NOS inhibitors,29 and low-dose endotoxin.30 Our data suggest that pregnancy confers a heightened vascular sensitivity to the depletion of ascorbate reserves.
The reason for the lack of effect of ascorbate intake on endothelium-mediated relaxation to ME or contractile response to PE remains unclear. This could involve differential sensitivity of myogenic- versus agonist-mediated vascular responses to components, such as NO, cyclooxygenase, and endothelial-derived hyperpolarizing factor.31 Perhaps in these arteries, PE and ME-mediated responses are less sensitive to changes in NO.
Vitamin C functions as a "first-line" antioxidant defense by scavenging reactive oxygen and nitrogen species, as well as antioxidant radicals.2 Our data are indirectly consistent with the hypothesis that reactive oxygen species, such as superoxide, may be decreasing NO bioavailability under conditions of lowered ascorbate and that pregnancy confers an increased sensitivity to this effect. Pretreatment of vessel preparations with antioxidants (Tiron or N-acetylcysteine) reversed the increased myogenic responsiveness of arteries from MS pregnant rats but had no effect on arteries from the other groups of animals, consistent with a role for reactive oxygen species in the reversal of the normal pregnancy-induced decrease in myogenic activity. Isolated aorta from the MS animals had significantly greater levels of superoxide compared with aortas from FS animals. Furthermore, plasma high-performance liquid chromatography concentrations were significantly increased in MS pregnant compared with FS pregnant rats but not in MS virgin compared with FS virgin, suggestive of oxidative stress in the setting of lowered ascorbate reserves during pregnancy.
Several lines of evidence suggest that normal human pregnancy is accompanied by oxidative stress that becomes additionally accentuated in women who develop preeclampsia.2,3,32 The ODS rat appears to differ in that plasma high-performance liquid chromatography concentrations are lower overall in the pregnant rather than the nonpregnant state. However, plasma high-performance liquid chromatography is a tissue-nonspecific measure reflecting extensive modification of circulating lipids.33
Vitamin C plays an important role in the formation of mature collagen and other connective tissue components, such as elastin.34 In this fashion, ascorbate plays a key role in the health of extracellular matrix important for vascular integrity. Distensibility and stress–strain characteristics of the arterial walls in our model revealed no differences by group, however, implying no overt differences in wall structure.
There has been controversy about whether vitamin C has any significant effect on plasma lipid levels in human beings. This is germane to preeclampsia, because the condition is accompanied by dyslipidemia (an accentuation of the lipid increases of normal pregnancy).3 Some studies have suggested that low vitamin C status may be a contributing factor to the elevation of cholesterol and triglycerides (reviewed in Hemila35). Our data, however, are not consistent with a strong relationship between short-term hypovitaminosis C and blood lipids.
One of the more intriguing aspects of our study is the 21% reduction in the average weight of fetuses in the MS group without a reduction in number of fetuses per pregnancy. In a human prospective cohort study, there was a 100 g difference in birth weight between the lowest and highest tertiles of maternal vitamin C intake in early pregnancy.36 Interestingly, several human studies have found a positive correlation between maternal plasma vitamin C concentrations and baby birth weight.37 Intrauterine growth restriction accompanies &30% to 40% of cases of preeclampsia. Maternal concentrations of plasma ascorbate are low at 20 weeks of gestation and throughout the remainder of pregnancy, not only in women who develop preeclampsia during the third trimester but also in women who remain normotensive but deliver small-for-gestational-age neonates.6 The decrease in vitamin C in these 2 pregnancy conditions tracks with persistently abnormal uterine artery Doppler waveform, concurring with the hypothesis that poor uteroplacental perfusion predisposes to oxidative stress.6 Additional investigation is clearly needed to determine the impact of maternal ascorbate status on fetal growth, placental development, and maternal blood pressure.
Perspectives
Preeclampsia is a human pregnancy-specific disorder that adversely affects the mother (by vascular endothelial dysfunction leading to hypertension, proteinuria, and edema) and the fetus (by intrauterine growth restriction). Maternal plasma concentrations of vitamin C are reduced in women with preeclampsia.7 In a pilot trial of women at risk of preeclampsia, the rate of preeclampsia was reduced by two thirds in the 70 women who took vitamins C and E compared with those who took placebo. Several larger, multicenter antioxidant trials are underway in which women will take vitamin C and E supplements or placebo from early pregnancy to test the effectiveness and safety of this treatment with regard to maternal and fetal outcome. Our data suggest that the maternal vasculature during pregnancy is particularly sensitive to moderate reductions in ascorbate, resulting in failure of the mesenteric artery myogenic response to transition from the nonpregnant phenotype (high myogenic tone) to the normal pregnancy phenotype (low myogenic tone). Fetal growth was also restricted. Furthermore, ex vivo incubation of arteries with antioxidants restored this adaptive cardiovascular response to normal pregnancy. The ascorbate-dependent rat may prove to be a valuable tool for exploring relationships among antioxidant nutrients, vascular function, and fetal growth as an adjunct to ongoing human studies of preeclampsia.
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Acknowledgments |
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This work was supported by National Institute of Child Health and Human Development grant HD-30367 and National Heart, Lung, and Blood Institute grant HL-64144.
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Footnotes |
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The first 2 authors contributed equally to this work.
Received October 4, 2005; first decision November 1, 2005; accepted December 14, 2005.
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