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1 Perinatal Research Centre, Departments of Obstetrics and Gynecology, and Physiology, University of Alberta, Edmonton, Canada T6G 2S2
2 Physiology, Centre for the Early Origins of Adult Health, School of Molecular and Biomedical Science, University of Adelaide, South Australia 5005, Australia
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Abstract |
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-nitro-L-arginine methyl ester (L-NAME; NO synthase inhibitor). Observed differences in the NO pathway at 7 months were investigated using exogenous superoxide dismutase (SOD) to reduce NO scavenging, and sodium nitroprusside (SNP; NO donor) to assess smooth muscle sensitivity to NO. Sensitivity to methacholine-induced endothelium-dependent relaxation was reduced in H offspring at 4 months (P < 0.05), but was not different among groups at 7 months. L-NAME reduced methacholine sensitivity in C (P < 0.01), H (P < 0.01) and NR (P < 0.05) offspring at 4 months, but at 7 months L-NAME reduced sensitivity in C (P < 0.05), tended to in NR (P= 0.055) but had no effect in H offspring. SOD did not alter sensitivity to methacholine in C, but increased sensitivity in H offspring (P < 0.01). SNP responses did not differ among groups. In summary, prenatal hypoxia, but not nutrient restriction impaired endothelium-dependent relaxation at 4 months, and reduced NO mediation of endothelial function at 7 months, in part through reduced NO bio-availability. Distinct effects following reduced maternal oxygen versus nutrition suggest that decreased oxygen supply during fetal life may specifically impact adult vascular function.
(Received 9 February 2005;
accepted after revision 15 March 2005;
first published online 17 March 2005)
Corresponding author S. T. Davidge: Perinatal Research Centre, 232 Heritage Medical Research Centre, University of Alberta, Edmonton, AB, Canada T6G 2S2. Email: sandra.davidge{at}ualberta.ca
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Introduction |
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Placental insufficiency, a major clinical cause of fetal growth restriction (Henriksen & Clausen, 2002), reduces the supply of both oxygen, and nutrients to the fetus (Owens et al. 1989). There is evidence that either undernutrition (Ozaki et al. 2000; Nishina et al. 2003) or hypoxia (Thompson & Weiner, 1999) in utero may influence fetal endothelial function. Endothelial function is also impaired in adult rat offspring following global undernutrition (Franco et al. 2002a,b), or protein restriction during pregnancy (Torrens et al. 2002; Brawley et al. 2003). Reduced production of (Franco et al. 2002a) and/or sensitivity to endothelium-derived nitric oxide (NO) (Ozaki et al. 2001; Brawley et al. 2003) may contribute to these effects on adult endothelial function. Although placental insufficiency reduces both oxygen and nutrient supply to the fetus, the effects of reduced fetal oxygen supply on adult endothelial function are currently less clear. In chickens, chronic hypoxia in ovo increased adult vascular contractile responses, but did not affect endothelium-dependent relaxation in response to acetylcholine in femoral artery branches (Ruijtenbeek et al. 2003). However, NO modulation of this vascular relaxation in response to acetylcholine was reduced in the hypoxic group (Ruijtenbeek et al. 2003). Thus, although there is evidence to suggest that chronic hypoxia during development may impact the adult vascular NO pathway, the consequences for endothelial function in mammals remain unclear.
To clarify the effects of prenatal hypoxia on postnatal endothelial function, we investigated the effects of chronic maternal hypoxia on endothelium-dependent relaxation in isolated mesenteric arteries from adult male offspring. Since food intake is reduced in pregnant rats exposed to hypoxia (Van Geijn et al. 1980; de Grauw et al. 1986; Gleed & Mortola, 1991; Williams et al. 2005), we also examined the effects of reduced maternal nutrition across the same period of gestation. We hypothesized that either reduced maternal oxygen, or nutrient supply during the third week of pregnancy would reduce endothelium-dependent relaxation in adult male offspring. Since the endothelium-derived vasodilators NO and prostacyclin are important regulators of resistance artery tone, we also specifically assessed the role of NO and prostaglandins in mediating endothelium-dependent relaxation.
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Methods |
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All procedures in this study were approved by the University of Alberta Animal Welfare Committee. Female Sprague Dawley rats were obtained at 3 months of age (Charles River, Quebec, Canada) and were mated within the animal facility after a minimum 1-week acclimatization. Pregnancy was confirmed by the presence of sperm in a vaginal smear examined microscopically the following morning, and this was considered day 0 of pregnancy (term = 22 days). All rats received food (standard lab rat chow) ad libitum from day 0–15 of pregnancy. On day 15, rats were randomized to control (C, n= 10), maternal hypoxia (H, n= 9) or maternal nutrient restriction (NR, n= 7) protocols. Throughout pregnancy, rats were housed individually in standard rat cages which were maintained in a clean conventional facility, with 60% humidity, a 12 h light : 12 h darkness light cycle, and ad libitum access to water. Control group rats were housed in room air, and fed ad libitum throughout pregnancy. Food intake, and weight gain were measured daily in all pregnant rats.
Maternal hypoxia or nutrient restriction protocols
As has previously been described (Williams et al. 2005), maternal oxygen supply was reduced during late gestation by placing rats housed in standard individual cages (Volume: 20.7 l) inside a plexiglass chamber (Volume: 140 l) on day 15 of pregnancy, which was maintained at 12% oxygen by continuous infusion of a mixture of nitrogen and compressed air, without additional infusion of carbon dioxide. The chamber was opened briefly once a day to weigh rats and food, and to clean cages. After reclosing the chamber, the oxygen concentration was decreased from 21% to 12% over 30–35 min. Oxygen concentration of the chamber was monitored throughout treatment using a portable oxygen analyser, which was calibrated daily (Hudson RCI, Temecula, CA, USA). For comparative purposes, pregnant rats randomized to the NR protocol were placed inside a second, identical plexiglass chamber on day 15 of pregnancy, which was continuously infused with compressed air. Oxygen concentration was checked periodically to ensure rats were exposed to 21% oxygen. Rats were fed 11.5 ± 1 g standard rat chow day–1, which was equivalent to the lowest food intake recorded in rats exposed to maternal hypoxia, and represented 40% of control food intake during this time. We have previously described in detail the effects of these treatments on maternal food intake and weight gain throughout pregnancy (Williams et al. 2005).
Postnatal animal care and tissue collection
Within 3–12 h of birth in all groups, all pups were weighed, and litters were reduced to 8 pups per dam in order to standardize postnatal nutrition among litters. All dams were housed in room air, and fed ad libitum while nursing pups. Offspring were weaned at 3 weeks of age, and aged within the animal facility, with ad libitum access to food, for use at 4 or 7 months of age. At each age, 1–2 male offspring per litter were randomly selected for vascular experiments. Female offspring generated in this study were used in a separate series of experiments. On the day of experiment, male offspring were anaesthetized by intraperitoneal injection of 42.25 mg kg–1 sodium pentobarbital (Somnotol, MTC Pharmaceuticals, Ontario, Canada) and killed by exsanguination. At this time, a section of the mesenteric arcade 5–10 cm distal from the pylorus was removed, and placed in ice-cold HEPES-buffered physiological saline solution (HEPES PSS, mM: NaCl 142.0, KCl 4.7, KH2PO4 1.18, MgSO4 1.17, CaCl2 1.56, Glucose 5.5, HEPES 10.0, pH 7.4) for subsequent artery dissection.
Wire myography for assessment of endothelial function
Second-order mesenteric arteries of 250–350 µm internal diameter were dissected free of fat and connective tissue, and cut into approximately 2-mm-long sections. Two 20 µm diameter wires were threaded through the lumen of each artery section, which was then mounted onto an isometric wire myograph system (Kent Scientific, Litchfield, CT) in a 5 ml organ bath containing warmed (37°C) HEPES–PSS. The length of each artery section was measured using a micrometer, and following a 30-minute equilibration period a passive circumference–tension curve was performed for each segment in order to set optimum resting tension. Arteries were then allowed a further 30-minute equilibration period. Cumulative concentration–response curves to the 
1 adrenergic receptor agonist phenylephrine (100–50 µM) were performed in order to preconstrict arteries to the same extent before measuring vasodilator responses. The concentration of phenylephrine required to produce 50% of the maximal vasoconstrictor response to this agonist was calculated for each artery, and this concentration was administered prior to performing vasodilation curves. Following a 30-minute wash period, arteries were preconstricted and cumulative concentration–response curves were then performed using the stable acetylcholine analogue acetyl-ß-methylcholine chloride (methacholine, 1 nM to 1 µM, Sigma), which produces an endothelium-dependent arterial relaxation. Methacholine concentration–response curves were then repeated following a 15 minute incubation with N-nitro-L-arginine methyl ester (L-NAME; nitric oxide synthase inhibitor, 100 µM, Calbiochem) or meclofenamic acid (meclofenamate, prostaglandin H synthase inhibitor, 1 µM, Sigma).
In 7-month offspring, additional experiments were performed to further investigate the differences observed in NO mediation of endothelium-dependent relaxation. Specifically, following a 30-minute wash period arteries were incubated for 1 h with polyethylene glycol-superoxide dismutase (SOD, 50 units ml–1, Sigma). Arteries were preconstricted with phenylephrine as above, prior to repeating methacholine concentration–response curves. We have previously validated this SOD protocol for use in wire myography preparations using both rat (Davidge et al. 1998; O'Brien et al. 2001) and mouse arteries (Cooke & Davidge, 2003). Vascular relaxation in response to the exogenous NO donor sodium nitroprusside (SNP, 1 nM to 1 µM) was also determined in arteries from 7-month offspring, in order to assess vascular smooth muscle sensitivity to NO.
Detection of endothelial nitric oxide synthase (eNOS) protein by immunofluorescence
The primary changes in vascular function observed in this study implicated changes in the endothelial NO pathway, therefore we determined relative staining for eNOS within mesenteric arteries using immunofluorescence. A small section of the mesenteric arcade was embedded in optimal cutting temperature (OCT) compound (Tissue-Tek) before being snap-frozen in liquid nitrogen and stored at –80°C. Frozen embedded tissue was sectioned (10 µm) using a cryostat (–20°C), and sections mounted on superfrost slides, which were wrapped in foil and stored at –80°C until used in immunofluorescence experiments. Slides were allowed to thaw to room temperature for 1 h prior to use. Non-specific antibody binding was blocked by incubating sections in 2% bovine serum albumin (BSA) in phosphate buffered saline (PBS) for 1 h. Experimental sections were then incubated with eNOS primary antibodies (1 : 100, Affinity Bioreagents, PA3-031) overnight at 4°C, while control sections on each slide were incubated with 2% BSA alone during this time. After slides were washed in PBS, they were incubated with a rhodamine-conjugated secondary antibody (Molecular Probes, A-11010). Slides were washed well, before being mounted with a DAPI-containing 2 : 1 Vectashield H-1200 mounting solution (Vector Laboratories Inc, Burlington, Ontario, Canada). Slides were then stored in the dark at 4°C before analysis (within 2 days) using an Olympus IX81 fluorescent microscope (Carson Scientific Imaging Group, Ontario, Canada). Mesenteric arteries were identified morphologically within sections, and images were captured using Slidebook 2D, 3D timelapse imaging software (Intelligent Imaging Innovations Inc, Colorado, USA). Sections from all groups were stained simultaneously, and images were renormalized after capture to display the same range of fluorescence intensity. Adobe Photoshop was used to perform densitometry analysis of eNOS staining. From each animal the relative intensity of staining within 2–7 arteries was determined, and subsequently averaged. Prior to performing these experiments the specificity of the eNOS antibody was confirmed within our laboratory using blocking peptides, and was subsequently confirmed by the endothelial localization within images.
Data analysis and statistics
Data are presented as means ±S.E.M. Neonatal characteristics were compared using one- or two-way ANOVA as appropriate and, where relevant, Tukey's post hoc analysis. Cumulative concentration–response curves were summarized for statistical purposes by calculation of EC50 values using the Hill slope equation (Sigma Plot 8.0 Pharmacology Standard Curves Analysis). The effect of treatment group on vascular sensitivity, as determined by comparison of the EC50 values, was assessed using one- or two-way ANOVA with Tukey's post hoc test. The effect of incubating arteries with inhibitors of NO or prostaglandin synthesis, or with SOD, on vascular responses to methacholine within groups was determined by use of Student's paired t test. Relative immunofluorescence staining levels are presented as median values, and were compared among groups using a Kruskal–Wallis ANOVA on ranks. Statistical significance was defined as P < 0.05.
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Results |
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The effects of the maternal hypoxia or nutrient restriction protocols used in this study on maternal food intake and weight gain during pregnancy, and on neonatal body weight and growth parameters have been described in detail previously (Williams et al. 2005). Prior to reduction of each litter to eight pups, litter size was not different among groups, however, birth weight was reduced by both maternal hypoxia (H) and nutrient restriction (NR), compared to control (C) (Table 1, P < 0.001). At both 4 and 7 months of age, male H offspring were significantly smaller than those from either C or NR dams (Table 1, P < 0.01).
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Mesenteric artery diameter was not different among groups at either 4 or 7 months of age (4 months: C, 296 ± 14 µm; H, 269 ± 16 µm; NR, 263 ± 19 µm; 7 months: C, 290 ± 12 µm; H, 270 ± 14 µm; NR, 305 ± 18 µm). At 4 months, sensitivity to the endothelium-dependent vasodilator methacholine was reduced in H offspring compared to either C or NR offspring (Fig. 1A, P < 0.05). At 7 months, however, the response to methacholine was not different among groups (Fig. 1B, P > 0.05). In C offspring, the vascular sensitivity to methacholine decreased between 4 and 7 months, as evidenced by the increased EC50 value (Fig. 1C, P < 0.05). There was no effect of increasing age on the endothelium-dependent relaxation of mesenteric arteries from H or NR offspring.
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Meclofenamate (prostaglandin H synthase inhibitor) reduced the vascular sensitivity to methacholine in 4-month-old NR offspring (EC50: 54.0 ± 8.4 nMversus 85.8 ± 21.7 nM, P < 0.05), but did not affect vascular relaxation in the other groups. Interestingly, at 7 months meclofenamate tended to increase sensitivity to methacholine-induced vasodilation in both H (EC50: 103.1 ± 30.1 nMversus 78.6 ± 28.5 nM, P= 0.06), and NR offspring (EC50: 61.1 ± 18.2 nMversus 36.0 ± 7.1 nM, P= 0.07), suggesting the inhibition of a vasoconstrictor as opposed to vasodilator prostaglandin.
Nitric oxide mediation of endothelium-dependent responses
At 4 months, L-NAME (NO synthase inhibitor) reduced the vascular sensitivity to methacholine in both C (Fig. 2A, EC50: 45.5 ± 12.1 nMversus 104.2 ± 25.9 nM, P < 0.01) and H offspring (Fig. 2B, EC50: 112.3 ± 17.7 nMversus 190.6 ± 21.9 nM, P < 0.01), but did not significantly change the EC50 value in NR offspring (Fig. 2C, EC50: 72.6 ± 30.2 nMversus 105.7 ± 25.5 nM, P= 0.08). The methacholine concentration–response curve was significantly shifted across the lower concentration range in NR offspring however, such that L-NAME significantly increased the EC20 value (Fig. 2C, EC20: 11.1 ± 3.3 nMversus 24.7 ± 7.6 nM, P < 0.05).
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Figure 6A–F shows representative images of vascular staining for eNOS in sections of mesenteric arteries from C, H and NR offspring at 4 and 7 months. The relative intensity of immunofluorescent staining for eNOS increased with increasing age in C offspring (P < 0.01, Fig. 6G), but not in either H or NR offspring. The relative staining intensity for eNOS was lower in arteries from NR offspring than from either C or H offspring at 7 months (P < 0.05, Fig. 6G).
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Discussion |
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Mesenteric arteries from 4-month H offspring were significantly less sensitive to endothelium-dependent relaxation in response to methacholine than either C or NR offspring. At this age, L-NAME reduced sensitivity to methacholine in all offspring, while meclofenamate did not affect methacholine sensitivity in either H or C offspring. While the degree of NO or prostaglandin mediation of methacholine-induced relaxation may vary among groups, our results do not suggest substantial differences in the contributions of these pathways in mesenteric arteries from 4-month H offspring. Our data may therefore imply that other mechanisms mediate the observed impairment in endothelial function.
In C offspring, mesenteric artery sensitivity to methacholine-induced endothelium-dependent relaxation decreased with increasing age. However, in arteries from H or NR offspring, methacholine EC50 values did not further shift with age, demonstrating no age-dependent change in endothelial sensitivity to methacholine. These data suggest a possible premature ageing of the vasculature in H and NR offspring. Previously, when the effects of moderate maternal undernutrition throughout pregnancy on endothelial function in femoral artery branches were examined in 3.5- and 7-month rat offspring, increasing age reduced maximal relaxation similarly in control, and restricted offspring (Ozaki et al. 2001). The lost interaction of age with endothelial function in NR offspring from the current study may reflect differences in the femoral versus mesenteric vascular beds, or the timing or severity of the undernutrition used in these studies.
Endothelium-dependent relaxation in C offspring was significantly mediated by NO at both 4 and 7 months, as L-NAME decreased arterial sensitivity to methacholine at both time-points. In NR offspring, L-NAME also tended to reduce sensitivity to methacholine at both ages. While the effect of L-NAME on the relaxation to methacholine in NR offspring at 7 months was more variable than in C or H offspring, these data suggest that the NO pathway contributes to endothelium-dependent relaxation in this group. In contrast, by 7 months there was no apparent role for NO in mediating vasodilatation in response to methacholine in H offspring. Interestingly, chronic hypoxia in ovo also reduced NO mediation of endothelium-dependent relaxation in femoral artery branches from chickens aged 14–15 weeks, without changing overall endothelial responses to acetylcholine (Ruijtenbeek et al. 2003). Endothelial NO production is important in regulating short-term vascular tone (Vallance et al. 1989; Coffman, 1994), arterial distensibility (Kinlay et al. 2001; Wilkinson et al. 2002), and vascular smooth muscle proliferation (Cornwell et al. 1994; Fukumoto et al. 1999). Changes in this pathway may therefore affect long-term cardiovascular health, and have been implicated in clinical hypertension (Linder et al. 1990; Panza et al. 1990). Impairments in the NO pathway have now also been implicated in the vascular dysfunction programmed through a range of dietary models of fetal growth restriction, including models of maternal protein (Torrens et al. 2002) and global (Franco et al. 2002a; Franco et al. 2004) undernutrition. Our data demonstrate that maternal hypoxia, associated with decreased appetite during late gestation also reduces NO mediation of endothelial function in adult offspring. However, offspring from pregnancies where maternal nutrition was similarly reduced during this time did not demonstrate reduced NO mediation of relaxation to methacholine. This suggests that hypoxia alone, or the interaction of hypoxia and undernutrition during the last week of pregnancy, impaired NO-mediated endothelial function in adult male rats.
To further investigate the loss of NO-mediated relaxation in 7-month-old H offspring, we determined the effect of exogenous SOD, which reduces the scavenging of NO by superoxide anion (Rubanyi & Vanhoutte, 1986; Davidge et al. 1998; Cooke & Davidge, 2003). In C offspring, the addition of SOD did not affect the response to methacholine, demonstrating that superoxide anion did not influence endothelial function in this group. In H offspring, the EC50 value was not significantly shifted, but the reduction in EC20 value by SOD suggests that local superoxide anion concentrations influence endothelium-dependent relaxation across the nanomolar agonist concentration range, which may be of physiological relevance. Enhanced vascular oxidative stress has previously been demonstrated to impair endothelial function in adult offspring from nutrient-restricted dams (Franco et al. 2002b); however, this is the first assessment in adult offspring following chronic hypoxia during development.
There were no differences in the vascular responses to the NO donor sodium nitroprusside among the three groups, suggesting that the loss of NO-mediated relaxation in H offspring is due to reduced bio-available NO rather than decreased vascular smooth muscle sensitivity to relaxation by NO. Undernutrition during pregnancy has previously been reported to increase (Holemans et al. 1999), decrease (Ozaki et al. 2001; Brawley et al. 2003) or not alter (Franco et al. 2002a; Franco et al. 2002b) vascular sensitivity to sodium nitroprusside; however, the causes of these heterogeneous effects are not yet clear.
In this study, the relative staining for eNOS increased with age only in C offspring. Previous studies have also demonstrated greater expression of eNOS protein in the aorta from old compared to young male rats, while both endothelium-dependent dilation in vivo and eNOS activity in the aorta (Cernadas et al. 1998; van der Loo et al. 2000), and mesenteric arteries (Matz et al. 2000) were reduced by ageing. Interestingly there was no significant increase in staining for eNOS with increasing age in the mesenteric arteries of either H or NR offspring, and at 7 months, staining for eNOS was lower in arteries from NR offspring than in either C or H offspring. Consistent with these findings, eNOS mRNA expression and enzyme activity were both reduced in the aorta following undernutrition throughout pregnancy (Franco et al. 2002a). The sustained endothelial eNOS expression in 7-month H offspring further supports data suggesting that the loss of NO-mediated endothelial function may result from decreased bio-available NO, rather than a reduced capacity to produce the vasodilator.
Finally, we also evaluated the role of prostaglandin production in mediating endothelium-dependent responses. Significant prostaglandin-mediated relaxation was only observed in the 4-month-old NR offspring. The trend for sensitivity to methacholine to be increased by meclofenamate in both H and NR offspring at 7 months of age suggests that in these groups there may be inhibition of a vasoconstrictor rather than vasodilator prostaglandin. It has previously been demonstrated that ageing increased production of vasoconstrictor, as opposed to vasodilator prostaglandins within the endothelium (Stewart et al. 2000), and it is possible that a similar change in the balance of prostanoid production may contribute to this observation. Endothelium-dependent vasodilation is also mediated by other factors, such as endothelium-derived hyperpolarizing factor(s). Our results suggest changes in this pathway may occur following reduced oxygen supply in utero.
In summary, chronic maternal hypoxia during pregnancy impaired endothelium-dependent relaxation in mesenteric arteries from 4-month offspring, which was not attributable to overt changes in the NO or prostaglandin pathways. Maternal hypoxia also reduced NO modulation of endothelium-dependent relaxation in 7-month offspring, when compared to C or NR offspring. These effects were not observed in NR offspring, where maternal nutrition was reduced during pregnancy to account for reduced appetite in H dams (Williams et al. 2005). Therefore, these data provide evidence that reduced oxygen supply during late gestation, either independently or through interaction with reduced nutrition, impacts adult endothelial function in a mammalian model. The causes of intrauterine growth restriction within human populations are heterogeneous, and frequently involve reduction of both fetal oxygen and nutrient supply. It is therefore important to recognize that the programming of later cardiovascular function, including endothelial function, may reflect the specific nature of the in utero environment.
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, n= 10), maternal hypoxia (H, 
, n= 7) or nutrient restriction dams (NR, grey triangles, n= 8). B, methacholine-induced endothelium-dependent relaxation in mesenteric arteries from 7-month offspring of control (C, n= 14), hypoxia (H, n= 12) or nutrient-restricted (NR, n= 6) dams. C, endothelial sensitivity to methacholine (EC50 values) in mesenteric arteries from offspring of control (C, open bars), hypoxia (H, filled bars) or nutrient-restricted dams (NR, grey bars) at 4 or 7 months. Different letters denote significant differences (P < 0.05) among groups. Error bars: S.E.M.
