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Original Article

Perinatal Resveratrol Supplementation to Spontaneously Hypertensive Rat Dams Mitigates the Development of Hypertension in Adult OffspringNovelty and Significance

Alison S. Care, Miranda M. Sung, Sareh Panahi, Ferrante S. Gragasin, Jason R.B. Dyck, Sandra T. Davidge, Stephane L. Bourque
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https://doi.org/10.1161/HYPERTENSIONAHA.115.06793
Hypertension. 2016;67:1038-1044
Originally published February 29, 2016
Alison S. Care
From the Department of Obstetrics and Gynecology (A.S.C., S.T.D.), Department of Pediatrics (M.M.S., J.R.B.D.), Department of Anesthesiology and Pain Medicine (S.P., F.S.G., S.L.B.), Department of Pharmacology (J.R.B.D., S.L.B.), Cardiovascular Research Centre (A.S.C., M.M.S., F.S.G., J.R.B.D., S.T.D., S.L.B.), Women and Children’s Health Research Institute (A.S.C., M.M.S., F.S.G., J.R.B.D., S.T.D., S.L.B.), University of Alberta, Edmonton, Alberta, Canada; and Robinson Research Institute, University of Adelaide, Adelaide, South Australia, Australia (A.S.C.).
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Miranda M. Sung
From the Department of Obstetrics and Gynecology (A.S.C., S.T.D.), Department of Pediatrics (M.M.S., J.R.B.D.), Department of Anesthesiology and Pain Medicine (S.P., F.S.G., S.L.B.), Department of Pharmacology (J.R.B.D., S.L.B.), Cardiovascular Research Centre (A.S.C., M.M.S., F.S.G., J.R.B.D., S.T.D., S.L.B.), Women and Children’s Health Research Institute (A.S.C., M.M.S., F.S.G., J.R.B.D., S.T.D., S.L.B.), University of Alberta, Edmonton, Alberta, Canada; and Robinson Research Institute, University of Adelaide, Adelaide, South Australia, Australia (A.S.C.).
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Sareh Panahi
From the Department of Obstetrics and Gynecology (A.S.C., S.T.D.), Department of Pediatrics (M.M.S., J.R.B.D.), Department of Anesthesiology and Pain Medicine (S.P., F.S.G., S.L.B.), Department of Pharmacology (J.R.B.D., S.L.B.), Cardiovascular Research Centre (A.S.C., M.M.S., F.S.G., J.R.B.D., S.T.D., S.L.B.), Women and Children’s Health Research Institute (A.S.C., M.M.S., F.S.G., J.R.B.D., S.T.D., S.L.B.), University of Alberta, Edmonton, Alberta, Canada; and Robinson Research Institute, University of Adelaide, Adelaide, South Australia, Australia (A.S.C.).
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Ferrante S. Gragasin
From the Department of Obstetrics and Gynecology (A.S.C., S.T.D.), Department of Pediatrics (M.M.S., J.R.B.D.), Department of Anesthesiology and Pain Medicine (S.P., F.S.G., S.L.B.), Department of Pharmacology (J.R.B.D., S.L.B.), Cardiovascular Research Centre (A.S.C., M.M.S., F.S.G., J.R.B.D., S.T.D., S.L.B.), Women and Children’s Health Research Institute (A.S.C., M.M.S., F.S.G., J.R.B.D., S.T.D., S.L.B.), University of Alberta, Edmonton, Alberta, Canada; and Robinson Research Institute, University of Adelaide, Adelaide, South Australia, Australia (A.S.C.).
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Jason R.B. Dyck
From the Department of Obstetrics and Gynecology (A.S.C., S.T.D.), Department of Pediatrics (M.M.S., J.R.B.D.), Department of Anesthesiology and Pain Medicine (S.P., F.S.G., S.L.B.), Department of Pharmacology (J.R.B.D., S.L.B.), Cardiovascular Research Centre (A.S.C., M.M.S., F.S.G., J.R.B.D., S.T.D., S.L.B.), Women and Children’s Health Research Institute (A.S.C., M.M.S., F.S.G., J.R.B.D., S.T.D., S.L.B.), University of Alberta, Edmonton, Alberta, Canada; and Robinson Research Institute, University of Adelaide, Adelaide, South Australia, Australia (A.S.C.).
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Sandra T. Davidge
From the Department of Obstetrics and Gynecology (A.S.C., S.T.D.), Department of Pediatrics (M.M.S., J.R.B.D.), Department of Anesthesiology and Pain Medicine (S.P., F.S.G., S.L.B.), Department of Pharmacology (J.R.B.D., S.L.B.), Cardiovascular Research Centre (A.S.C., M.M.S., F.S.G., J.R.B.D., S.T.D., S.L.B.), Women and Children’s Health Research Institute (A.S.C., M.M.S., F.S.G., J.R.B.D., S.T.D., S.L.B.), University of Alberta, Edmonton, Alberta, Canada; and Robinson Research Institute, University of Adelaide, Adelaide, South Australia, Australia (A.S.C.).
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Stephane L. Bourque
From the Department of Obstetrics and Gynecology (A.S.C., S.T.D.), Department of Pediatrics (M.M.S., J.R.B.D.), Department of Anesthesiology and Pain Medicine (S.P., F.S.G., S.L.B.), Department of Pharmacology (J.R.B.D., S.L.B.), Cardiovascular Research Centre (A.S.C., M.M.S., F.S.G., J.R.B.D., S.T.D., S.L.B.), Women and Children’s Health Research Institute (A.S.C., M.M.S., F.S.G., J.R.B.D., S.T.D., S.L.B.), University of Alberta, Edmonton, Alberta, Canada; and Robinson Research Institute, University of Adelaide, Adelaide, South Australia, Australia (A.S.C.).
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Abstract

This study was undertaken to determine whether perinatal maternal resveratrol (Resv)—a phytoalexin known to confer cardiovascular protection—could prevent the development of hypertension and improve vascular function in adult spontaneously hypertensive rat offspring. Dams were fed either a control or Resv-supplemented diet (4 g/kg diet) from gestational day 0.5 until postnatal day 21. Indwelling catheters were used to assess blood pressure and vascular function in vivo; wire myography was used to assess vascular reactivity ex vivo. Perinatal Resv supplementation in dams had no effect on fetal body weights, albeit continued maternal treatment postnatally resulted in growth restriction in offspring by postnatal day 21; growth restriction was no longer evident after 5 weeks of age. Maternal perinatal Resv supplementation prevented the onset of hypertension in adult offspring (−18 mm Hg; P=0.007), and nitric oxide synthase inhibition (with l-NG-nitroarginine methyl ester) normalized these blood pressure differences, suggesting improved nitric oxide bioavailability underlies the hemodynamic alterations in the Resv-treated offspring. In vivo and ex vivo, vascular responses to methylcholine were not different between treatment groups, but prior treatment with l-NG-nitroarginine methyl ester attenuated the vasodilation in untreated, but not Resv-treated adult offspring, suggesting a shift toward nitric oxide–independent vascular control mechanisms in the treated group. Finally, bioconversion of the inactive precursor big endothelin-1 to active endothelin-1 in isolated mesenteric arteries was reduced in Resv-treated offspring (−28%; P<0.05), and this difference could be normalized by l-NG-nitroarginine methyl ester treatment. In conclusion, perinatal maternal Resv supplementation mitigated the development of hypertension and causes persistent alterations in vascular responsiveness in spontaneously hypertensive rats.

  • developmental programming
  • hypertension
  • nitric oxide
  • prevention
  • resveratrol
  • spontaneously hypertensive rat
  • vascular function

Introduction

See Editorial Commentary, pp 829–830

Hypertension is an important and modifiable risk factor for cardiovascular disease, affecting ≈1 in 4 adults worldwide.1 In the United States, hypertension is estimated to account for >$46 billion annually in healthcare services, medication, and lost productivity,2 and these costs are expected to increase substantially over the coming decades. A universal consensus is that prevention, rather than treatment, is a more strategic and cost-effective approach to reducing the burden of cardiovascular disease in coming decades.

Essential hypertension, in which known primary causes (eg, renovascular disease, pheochromocytoma, monogenic causes, etc) are not present, makes up 95% of hypertension worldwide.3 Although the pathogenesis of essential hypertension is multifactorial and complex, subclinical changes in vascular function often precede the development of hypertension and circulatory decline.4 The spontaneously hypertensive rat (SHR) is a model of essential hypertension in which blood pressure (BP) begins to rise after 6 weeks of age, ultimately reaching stable pressures of ≈180 to 200 mm Hg. Recently, Komolova et al reported evidence of altered vascular resistance profiles and renal hemodynamics as early as 3 weeks of age in the SHR,5 implicating these early functional changes as a cause, rather than a consequence, of hypertension in this model. As such, the developmental period before weaning (ie, before 3 weeks) may constitute a critical time for therapeutic intervention.

Accumulating evidence from human and animal studies suggests that an important determinant of chronic disease risk is dictated by the quality of the intrauterine environment.6 Because of its phenotypic plasticity, the fetus and neonate are highly susceptible to several insults, including hypoxia, nutritional disturbances, and hormonal influences.6 By extension, this period of increased vulnerability also reflects a time in which offspring may be most amenable to therapeutics,7 such that targeted interventions may provide lasting benefits, even after treatment cessation.

Resveratrol (Resv) is a natural polyphenol found in relatively high concentrations in grapes and other plants. Studies in rodent models have shown that Resv confers protection against cardiovascular diseases and other chronic health conditions.8 Resv treatment has been shown to lower BP and improve nitric oxide (NO) bioavailability (and hence improved vascular function) in adult SHR,9,10 albeit these beneficial cardiovascular effects were lost when treatment was discontinued.10 Here we investigated whether maternal Resv supplementation instituted during gestation and the immediate postnatal phase would have lasting benefits on BP regulation and vascular function in SHR offspring.

Methods and Materials

Methods are available in the online-only Data Supplement.

Animals and Treatments

The experimental protocols described herein were approved by the University of Alberta Animal Care and Use Committee, in accordance with the Canadian Council on Animal Care guidelines. SHR were purchased from Charles River (St Constant, QC) at 12 weeks of age and were mated with male SHRs. After confirmation of pregnancy, dams were randomly assigned to receive either a control diet (AIN-93G, Research Diets Inc, New Brunswick, NJ) or an identical diet supplemented with Resv (Lalilab, Durham, NC; 4 g/kg diet). Dams were maintained on their respective diet until postnatal day 21. After giving birth, rats were left undisturbed to minimize maternal stress. Offspring were weaned onto a standard chow-based diet at postnatal day 21.

Statistical Analyses

Initially, all offspring data from male and female offspring were analyzed separately. However, no sex differences were observed throughout, and therefore, results from both sexes from each litter were pooled. Experimental number represents fetuses or offspring from different dams. Data were analyzed by Student’s t test or 2-way analysis of variance with Bonferroni post hoc test, as appropriate. For isolated vascular function data, pEC50 values from concentration response curves were calculated by fitting to the Hill equation; comparisons between untreated vessels and those preincubated with antagonists were compared by analysis of variance, with Bonferroni correction. Summary data for big endothelin-1 (bET-1) concentration–response curves were calculated as area under the curve for each curve and compared by Student’s t test or 2-way analysis of variance. Data are presented as mean±SEM. P<0.05 was considered significant.

Results

Pregnancy Outcomes

Resv supplementation had no effect on maternal food intake (Figure S1A in the online-only Data Supplement) or body weight gain (Figure S1B) throughout pregnancy. No differences were observed in uterine artery resistance index (SHR: 0.61±0.02, n=8; SHR+Resv: 0.59±0.04, n=5; P=0.61) and pulsatility index (SHR: 0.62±0.02, n=5; SHR+Resv: 0.59±0.04, n=5; P=0.51) or umbilical artery pulsatility index (SHR: 0.97±0.01, n=5; SHR+Resv: 0.96±0.01, n=5; P=0.69) between SHR and their Resv-treated counterparts, suggesting that prenatal Resv treatment had no effect on blood flow patterns in the maternal uterine arteries (which supply blood to the conceptus) or in the umbilical arteries (as an indicator of fetal blood supply). Length of gestation was not different between treatment groups (with 4 and 7 litters in the SHR group giving birth on gestational day [GD] 21 and GD22, respectively, and 2 and 9 litters in the SHR+Resv group giving birth on GD21 and GD22, respectively; P=0.63 by Fisher exact test), nor were litter sizes (SHR: 8.1±1.6, n=7; SHR+Resv: 7.6±1.6, n=5; P=0.81). Maternal Resv treatment throughout pregnancy had no effects on fetal body weights or placental weights (shown as litter averages in Table S1); analysis of individual pup body weights (SHR: 4.03±0.06 g, n=36; SHR+Resv: 4.04±0.07 g, n=38; P=0.95) and placental weights (SHR: 0.37±0.01 g, n=36; SHR+Resv: 0.39±0.01 g, n=38; P=0.10), although not different, were calculated to ensure that averaging of litters did not conceal intralitter variability. Organ weights (absolute and normalized to body weight) were not different between groups at GD21, with the exception that male SHR+Resv fetuses had increased heart weights (P=0.034), but this difference was no longer significant when normalized to body weight (P=0.074; Table S1).

Postnatal Growth Patterns in SHR Offspring

Continued supplementation of maternal diet with Resv postpartum resulted in growth restriction by postnatal day 21, corresponding to 17% reduction in offspring body weights (P<0.01; Figure 1) compared with untreated SHR; male and female offspring exhibited nearly identical growth patterns (Figure S2). After offspring were weaned, serum prolactin levels and glucose handling in dams were assessed to gain insights into the effects of Resv supplementation on maternal health. Serum prolactin levels in dams were not different between groups (SHR: 7.3±1.1 ng/mL, n=4; SHR+Resv: 11.6±2.3 ng/mL, n=4; P=0.15). Further, glucose tolerance test testing in dams within 2 days of weaning offspring revealed a trend toward glucose intolerance in Resv-fed dams (glucose tolerance test area under the curve: SHR: 59.84±9.83, n=5; SHR+Resv: 90.2±9.7, n=5; P=0.06).

Figure 1.
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Figure 1.

Combined male and female offspring growth patterns expressed as percent of respective untreated spontaneously hypertensive rat (SHR) body weights. *P<0.001 versus SHR offspring. BW indicates body weight; and Resv, resveratrol.

No differences in body weight were evident at 5 weeks of age (Figure 1). At the time of euthanasia (≈20 weeks), body weight, length, and organ weights were not different between treatment groups (Table S2). To determine whether SHR+Resv–altered growth patterns were associated with changes in body composition or altered metabolic profile in adulthood, we assessed body composition and performed glucose tolerance tests before euthanasia; no differences in body composition were evident between treatment groups (Table S2), and there was no evidence of altered glucose handling in SHR or SHR+Resv adult offspring (Figure S3).

Cardiovascular Outcomes

No sex differences in hemodynamics were observed, and therefore, male and female offspring data from each litter were pooled. Adult SHR+Resv offspring had lower baseline hemodynamics than their respective SHR counterparts (Figure 2), including mean (−17 mm Hg; P=0.007), diastolic (−18 mm Hg; P=0.007), and systolic BPs (−15 mm Hg; P=0.02). Neither pulse pressures (SHR: 53±4, n=10; SHR+Resv: 56±3, n=7; P=0.60) nor heart rates (SHR: 366±7, n=10; SHR+Resv: 351±5, n=7; P=0.15) were different between treatment groups. Data separated according to sex are shown in Figure S4.

Figure 2.
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Figure 2.

Baseline mean blood pressure (BP; A), diastolic BP (B), and systolic BP (C) values of adult spontaneously hypertensive rat (SHR) and SHR+Resv offspring at ≈20 weeks of age. Resv indicates resveratrol.

Administration of 0.1, 1, and 10 μg/kg methylcholine (MCh) caused dose-dependent reductions in mean, diastolic, and systolic BP (Figure S5A). However, the dose of 10 μg/kg MCh, but not 0.1 or 1 μg/kg, caused a marked, albeit transient, reduction in heart rate (P<0.001; Figure S5B), suggesting that this dose impacts cardiac autonomic function. To avoid the confounding effects of reduced cardiac output on hemodynamics, we focused instead on MCh doses of 0.1 and 1 μg/kg. Although there was a dose-dependent lowering effect by MCh (P<0.001), there was no difference between SHR and SHR+Resv offspring (Figure S6A–S6C).

Adult offspring were then treated with the nitric oxide synthase inhibitor l-NG-nitroarginine methyl ester (l-NAME) to study the role of NO. l-NAME administration caused a hypertensive response, and this rise in diastolic and mean BP were greater in SHR+Resv than in SHR offspring (Figure 3A and 3B); the rise in systolic BP was not different between groups (Figure 3C). Subsequent administration of MCh in the presence of l-NAME caused a dose-dependent drop in all hemodynamic parameters in both groups, but diastolic and mean BP drops were greater in SHR+Resv compared with SHR offspring (Figure S6D–S6F). As MCh-induced hypotension was not different between perinatal treatment groups (Figure S6A–S6C), the calculated shift in the MCh-induced BP lowering with and without l-NAME was greater in SHR+Resv than in SHR offspring (Figure 4). Finally, to determine whether endothelin-1 (ET-1) production was altered by changes in NO signaling, a subgroup of rats were treated with the endothelin-converting enzyme inhibitor CGS 35066 (CGS) before l-NAME administration. Pretreatment with CGS partially attenuated the l-NAME-induced rise in diastolic BP (P=0.05), albeit by similar amounts in SHR and SHR+Resv offspring (Figure S7). In contrast, CGS had no apparent effects on mean or systolic BPs, suggesting that bET-1 conversion to active ET-1 is not altered in vivo.

Figure 3.
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Figure 3.

l-NG-nitroarginine methyl ester (l-NAME)–induced rise in mean blood pressure (BP; A), diastolic BP (B), and systolic BP (C). Rise in each hemodynamic parameter was taken as the highest value recorded (continuous average of 30 seconds) within the 15 minutes after l-NAME (30 mg/kg IV initial dose, followed after 10 minutes by 15 mg/kg IV maintenance dose) administration. Mean BP (A), diastolic BP (B), and systolic BP (C), assessed as percentage of baseline BP. Resv indicates resveratrol.

Figure 4.
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Figure 4.

Change in mean blood pressure (BP; A), diastolic BP (B), and systolic BP (C) in response to methylcholine (MCh) between l-NG-nitroarginine methyl ester (l-NAME) and vehicle conditions (data shown in Figure S6) to show NO contribution to vasodilation. *P<0.05 compared with spontaneously hypertensive rat (SHR) offspring at the same dose of MCh. Mean BP (A), diastolic BP (B), nd systolic BP (C), assessed as percentage of baseline BP. Resv indicates resveratrol.

To further study the altered vascular signaling pathways in adult offspring, we assessed vascular function in isolated mesenteric arteries. Cumulative concentration–response curves to the α-adrenoceptor agonist phenylephrine (Figure S8A) and ET-1 (Figure S8B) were superimposable between SHR and SHR+Resv offspring. Pretreatment with l-NAME potentiated these vasoconstrictor effects, albeit to a similar extent in SHR and SHR+Resv offspring (Figure S8). In the absence of inhibitors, there were no differences in cumulative concentration–response curves to MCh between SHR and SHR+Resv adult offspring (Figure 5A). However, pretreatment with l-NAME caused a shift in SHR offspring MCh curves (P<0.01) that was absent in SHR+Resv offspring (Figure 5A), suggesting loss of vascular NO signaling in this latter group. We next investigated whether vascular responses to the inactive precursor bET-1, which must be cleaved to yield a functional vasoconstrictor peptide,11 were altered because of maternal perinatal Resv treatment. SHR+Resv offspring had reduced bET-1 conversion to ET-1 (area under the curve −28%; P<0.05) compared with SHR offspring (Figure 5B). Pretreatment with l-NAME potentiated bET-1-induced vasoconstriction (P<0.001; Figure 5B), and this effect was more pronounced in SHR+Resv offspring compared with untreated offspring (SHR: +29±12%, SHR+Resv: +73±8%; P=0.02) such that bET-1-induced vasoconstriction was no longer different between groups (P=0.63).

Figure 5.
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Figure 5.

Ex vivo cumulative concentrations–response curves to methylcholine (MCh; A) and the inactive precursor big-ET-1 (bET-1; B) in isolated mesenteric arteries. Left, Cumulative concentration–response curves. Right, Summarized data; summarized data are shown as pEC50 (−logEC50) for sigmoidal curves for MCh and area under the curve (AUC) for the nonsigmoidal bET-1 curve. *P<0.05, **P<0.01, ***P<0.001 compared to vehicle in same perinatal treatment group. l-NAME indicates l-NG-nitroarginine methyl ester; Resv, resveratrol; and Veh, vehicle.

Discussion

In this study, we found that maternal Resv treatment throughout pregnancy caused (1) no effects on fetal growth patterns. Furthermore, continued Resv supplementation in the postnatal (preweaning) period caused (2) growth restriction in the offspring by 3 weeks of age; (3) prevented the development of hypertension in adult offspring; and finally, (4) caused persistent alterations in NO signaling in vivo and ex vivo. Taken together, these results suggest that hypertension in the SHR is amenable to early intervention, and Resv constitutes a promising candidate for early intervention to reduce future cardiovascular disease risks. However, as discussed later, care should be taken with the use of Resv during development because it may adversely affect neonatal growth as well as long-term cardiovascular outcomes.

The timing and duration of Resv treatment was chosen to maximize offspring exposure during the key periods of growth and development; rats are highly altricial, and thus, organ development continues until the third postnatal week. Moreover, recent work by Komolova et al showed vascular changes are evident as early as 3 weeks of age,5 implicating the period before weaning as an important determinant in the development of hypertension in this model.

Maternal Resv supplementation during pregnancy at 4 g/kg diet—which improves pregnancy outcomes in a model of severe hypoxia12—did not affect fetal growth trajectories in this study. These findings are consistent with our observations that Resv had little impact on uterine artery and fetal umbilical blood flow patterns. However, whether Resv supplementation improved maternal BP during pregnancy, as it does in adult SHR,9,10 is not known and is a limitation of the present study given that maternal hypertension can influence offspring BP with minimal impact on growth patterns.13 Interestingly, Roberts et al recently reported that Resv supplementation during pregnancy at a dose similar to that used in the present study affected pancreatic growth in nonhuman primates.14 Although pancreas weights were not assessed herein, there was no evidence of metabolic dysfunction or altered glucose homeostasis in adult SHR+Resv offspring, suggesting no obvious pancreatic dysfunction. More detailed studies pertaining to the effects of Resv on fetal growth and development are nevertheless warranted.

Continued maternal Resv treatment caused growth restriction in offspring in the postnatal phase, suggesting either a direct effect on offspring growth that is time-dependent or an indirect effect via the dam (eg, Resv may impact the quantity or quality of milk production via altered prolactin synthesis15,16). Although we did not detect any changes in maternal serum prolactin levels in the first day after offspring were weaned, it is possible that a more thorough investigation will reveal time-dependent changes. Resv has also been shown to impact metabolic function in rats,17 which in turn can influence milk quantity and composition. Our data in a small subset of dams suggest that metabolic function may be altered in dams during lactation. Irrespective of the cause of altered growth in the offspring, SHR+Resv offspring exhibited no apparent changes in body composition or glucose handling in adulthood, suggesting that these altered growth trajectories in early life do not appreciably impact metabolic function in adulthood. Whether underlying metabolic differences ultimately manifest with increasing age (or other metabolic stressors) remains to be determined.

The key finding that maternal Resv supplementation during development caused lower BP in adult offspring is among a few that demonstrate early interventions can impact the development of hypertension in the SHR. Previous studies have shown that Resv treatment instituted postweaning (eg, starting at 3–4 weeks) or later (eg, 10 week of age) successfully lowered BP in SHR,9,10,18 although there was reversion to a hypertensive state on cessation of treatment.10 These findings suggest that targeting the developmental period with Resv is critical to its long-term effects.

Improved NO bioavailability in the vasculature has been proposed to be an important mechanism by which continued Resv supplementation improves cardiovascular function9,10,18 and prevents pathological vascular remodeling.19 The finding that l-NAME caused a greater rise in BP, effectively normalizing BPs between SHR and SHR+Resv, suggests that a key mechanism by which Resv causes long-term BP normalization is restoration of NO-mediated signaling. To gain insights into the effects of maternal Resv treatment on adult offspring vascular function, we assessed hemodynamic responses to the endothelial-dependent vasodilator MCh in the presence and absence of l-NAME. Interestingly, we found that although MCh-induced vasodilation was not changed between SHR and SHR+Resv offspring, the involvement of NO-dependent pathways in this response is reduced in the SHR+Resv group. Total peripheral resistance is dictated, in large part, by arterioles that exhibit dependence on both NO-dependent and -independent mechanisms, and these findings suggest Resv treatment during development causes a shift toward non–NO dependent mechanisms. The relative contribution of NO-dependent and -independent mechanisms of vascular control seems to be plastic and, thus, permanently altered by influences during pregnancy. For example, prenatal hypoxia has been shown to reduce NO dependence in vascular tone and promote endothelial-derived hyperpolarization–mediated vasodilation.20 Whether this shift in vascular control mechanisms by Resv supplementation during development is mediated by hypoxia-related signaling is an intriguing hypothesis, particularly because Resv is known to interfere with hypoxia-inducible factor expression and adaptations to hypoxia.21

In addition to contributing to resting vascular tone, NO has myriad functions, including physiological antagonism of vasoactive mediators, such as ET-1.11 We have previously shown that NO modulates cleavage of bET-1 to active ET-1,22 and this pathway is perturbed in offspring that exhibit a reduced NO-mediated vasodilation.20,23 We therefore investigated the role of bET-1 conversion to active ET-1 in baseline and l-NAME-induced hypertension in adult offspring. The endothelin-converting enzyme inhibitor CGS attenuated the l-NAME–induced rise in BP, without affecting baseline BP, thus confirming our previous reports that NO tonically inhibits the actions of ET-1, in part by inhibiting the conversion of bET-1 to active ET-1.22 However, because CGS did not differentially affect the l-NAME-induced hypertension between groups, it is likely that baseline levels of bET-1 conversion do not appreciably contribute to the persistent lowering of BP.

We sought to gain further insights into the mechanisms underlying this altered vasodilatory pathway by investigating vascular signaling pathways in isolated mesenteric arteries. Consistent with our findings in vivo, MCh-induced vasodilation was unchanged between SHR and SHR+Resv offspring. However, the contribution of NO to this vasodilation was reduced in the SHR+Resv group, based on the lack of shift in EC50 by l-NAME in this group. These findings further support the notion of a greater dependence on NO-independent vascular control mechanisms in the treated offspring. In contrast, l-NAME potentiated vasoconstrictor responses to phenylephrine and ET-1 by comparable amounts in both treatment groups, suggesting residual amounts of NO signaling in blood vessels of SHR+Resv offspring. In fact, we found that bET-1 conversion to active ET-1 is attenuated in SHR+Resv offspring, and this difference between groups could be normalized with l-NAME pretreatment. Because we observed no changes in vasoconstrictor activity to phenylephrine nor ET-1—suggesting unaltered intrinsic vasoconstrictor mechanism and ET-1 receptor signaling in SHR+Resv offspring—these findings suggests improved NO signaling in the context of bET-1 bioconversion in the vasculature of treated offspring. Although this may seem at odds with the in vivo and ex vivo vascular function data showing a shift away from NO-dependent mechanisms, these findings may indicate that different subcellular compartments are more or less vulnerable to loss of NO signaling. Indeed, we have previously shown that levels of NO required to inhibit ET-1 signaling are lower than those needed to induce vasodilation,22 suggesting an intimate coupling between NOS enzymes and the ET-1 synthetic machinery. Future studies are needed to provide more definitive insights into this area of vascular biology.

It is particularly noteworthy that male and female offspring were similarly affected by the perinatal maternal Resv supplementation, considering how developmental stressors can induce a range of sexually dimorphic effects on cardiovascular function in the offspring.24 In many instances, gender-disparities do not manifest until advanced age,24 and thus, sex-differences in long-term cardiovascular function may become evident with time. Alternatively, it may be that Resv treatment prevents early events in the eventual progression to hypertension in the SHR that are common to both sexes. In either case, these results emphasize the need for additional studies focused on early mechanisms by which Resv impacts development, as well as long-term studies investigating the progression of the cardiovascular phenotype with advanced age.

Perspectives

This study offers new insights into therapeutic potential for Resv to prevent the development of hypertension in a model of essential hypertension. Although the mechanisms underlying this improvement in hemodynamics require further investigation, the degree of BP lowering was notable and likely impact long-term cardiovascular health in these offspring. Indeed, the average lifespan of the SHRs is ≈14 months, which ultimately ends prematurely because of cardiovascular complications associated with unmitigated hypertension. Although rats in the present study were euthanized for cardiovascular assessments, it would be of interest to determine whether perinatal maternal Resv treatment extends lifespan because even reductions of 2 to 3 mm Hg have been shown to reduce morbidity and mortality in humans.25 However, it is noteworthy that Racasan et al showed that although prenatal losartan treatment attenuated the development of hypertension in young SHR, these offspring ultimately developed malignant hypertension and died prematurely.26 In the case of SHR+Resv offspring, it is possible that despite maintaining vasodilatory function, the loss of vascular NO signaling may affect vascular health and contribute to accelerated age-related decline in circulatory function. As such, future studies examining the long-term cardiovascular health of prenatal or perinatal Resv treatment are crucial.

Sources of Funding

This work is funded by grants from the Canadian Institutes of Health Research and the Women and Children’s Health Research Institute. A.S. Care was supported by fellowships from the National Health and Medical Research Council of Australia, Alberta Innovates-Health Solutions, and the Heart and Stroke Foundation of Canada; S.T. Davidge is a Canada Research Chair in Maternal and Perinatal Cardiovascular Health.

Disclosures

None.

Footnotes

  • The online-only Data Supplement is available with this article at http://hyper.ahajournals.org/lookup/suppl/doi:10.1161/HYPERTENSIONAHA.115.06793/-/DC1.

  • Received November 9, 2015.
  • Revision received November 23, 2015.
  • Accepted January 5, 2016.
  • © 2016 American Heart Association, Inc.

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Novelty and Significance

What Is New?

  • Perinatal maternal resveratrol supplementation prevented the development of hypertension in adult spontaneously hypertensive rat offspring.

  • Alterations in nitric oxide signaling contribute to this resveratrol-mediated persistent lowering of blood pressure in adult spontaneously hypertensive rat offspring.

  • Postnatal (preweaning) resveratrol supplementation caused growth restriction in young spontaneously hypertensive rat offspring.

  • Male and female offspring are similarly affected by perinatal resveratrol treatment.

What Is Relevant?

  • Hypertension affects ≈25% of adults globally and is an important risk factor for cardiovascular disease. A universal consensus is that prevention of hypertension is a more strategic and cost-effective approach than treatment. The results of the present study demonstrate that resveratrol is a strong candidate for prenatal use as a prevention strategy for hypertension.

Summary

We demonstrate that perinatal maternal resveratrol supplementation prevents the rise in blood pressure and has persistent effects on vascular function in adult offspring.

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Hypertension
May 2016, Volume 67, Issue 5
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    Perinatal Resveratrol Supplementation to Spontaneously Hypertensive Rat Dams Mitigates the Development of Hypertension in Adult OffspringNovelty and Significance
    Alison S. Care, Miranda M. Sung, Sareh Panahi, Ferrante S. Gragasin, Jason R.B. Dyck, Sandra T. Davidge and Stephane L. Bourque
    Hypertension. 2016;67:1038-1044, originally published February 29, 2016
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    Perinatal Resveratrol Supplementation to Spontaneously Hypertensive Rat Dams Mitigates the Development of Hypertension in Adult OffspringNovelty and Significance
    Alison S. Care, Miranda M. Sung, Sareh Panahi, Ferrante S. Gragasin, Jason R.B. Dyck, Sandra T. Davidge and Stephane L. Bourque
    Hypertension. 2016;67:1038-1044, originally published February 29, 2016
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