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BOR - Papers in Press, published online ahead of print December 15, 2004.
Biol Reprod 2004, 10.1095/biolreprod.104.035675
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BIOLOGY OF REPRODUCTION 72, 997–1003 (2005)
DOI: 10.1095/biolreprod.104.035675
© 2005 by the Society for the Study of Reproduction, Inc.

Increased Myogenic Responses in Uterine but not Mesenteric Arteries from Pregnant Offspring of Diet-Restricted Rat Dams1

Denise G. Hemmings3,4, Sukrutha Veerareddy3,4,5,, Philip N. Baker5, and Sandra T. Davidge2,4

Department of Obstetrics and Gynecology,4 Perinatal Research Centre, University of Alberta, Edmonton, Alberta Canada, T6G 2S2 Maternal and Fetal Health Research Centre,5 University of Manchester, St. Mary's Hospital, Whitworth Park, Manchester M13 0JH, United Kingdom


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Results of epidemiological and animal studies suggest a link between poor in utero growth and cardiovascular disease in adult offspring. Few studies, however, have examined the effects of maternal undernutrition on the vasculature of pregnant female offspring, and to our knowledge, no studies have examined myogenic responses, which are essential to vascular tone development, in these animal models. Thus, myogenic responses were assessed in radial uterine arteries of pregnant female offspring to determine if diet restriction during pregnancy could contribute to transgenerational effects. These results were compared to those in mesenteric arteries, which greatly contribute to peripheral vascular resistance. Myogenic responses in the presence and absence of inhibitors for nitric oxide synthase (NOS) and prostaglandin H synthase (PGHS) were measured in arteries isolated from pregnant, 3-mo-old female offspring of control-fed (Coff) and globally diet-restricted (DRoff) rat dams. Although no differences were found in pregnancy weight gain, litter size, or fetal weights, placental size was significantly reduced in DRoff compared to Coff. Enhanced myogenic reactivity was observed at the highest pressure tested (110 mm Hg) in uterine, but not in mesenteric, arteries from DRoff compared to Coff. Inhibition of NOS, but not of PGHS, significantly increased myogenic responses in uterine arteries at pressures greater than 80 mm Hg in Coff but, interestingly, not in DRoff compared to untreated uterine arteries. Thus, impaired uterine vascular function in diet-restricted pregnant rat dams, which leads to similar impairment in their pregnant offspring, may be a mechanism through which transgenerational effects of unhealthy pregnancies occur.

developmental biology, nitric oxide, placenta, pregnancy, uterus


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Results of human epidemiological and animal studies suggest that an adverse prenatal environment plays a role in the origin of long-term health outcomes in the offspring [1]. The effects on the offspring may be consequences of "fetal programming," where the in utero environment delivers an insult at a critical early developmental period that leads to permanent effects on a range of physiological processes extending into adult life [2]. Indeed, protein and global diet restriction imposed during pregnancy in animal models result in elevated blood pressure [3–5], insulin resistance and metabolic syndrome [6], and vascular dysfunction [4, 5, 7, 8], all of which are important parameters in human disease, in the adult offspring. Furthermore, altered reproductive performance of the first-generation offspring may lead to transgenerational effects [9–12]. Therefore, evaluation of reproductive performance in pregnant female offspring who themselves developed in an adverse intrauterine environment is important. Altered vascular function in the uteroplacental and systemic circulation of pregnant female offspring may have consequences for the growing fetus and, thus, further contribute to transgenerational effects.

Perturbations of maternal vascular adaptations have been observed during conditions of malnourishment. Reduction of cardiac output [13], plasma volume [14], and a consequent fall in uteroplacental perfusion [13] were observed in pregnant rats subjected to global undernutrition. Reduced vasodilatory responses in uterine [15, 16] and mesenteric [17] arteries of diet-restricted (DR) pregnant rats may contribute to impaired vascular adaptations to pregnancy and reduced fetal weights. When these growth-restricted offspring mature and become pregnant, they also show impaired vasodilatory responses in the mesenteric bed [18]. However, to our knowledge, the uteroplacental vasculature of these pregnant offspring, which may affect fetal growth and adult vascular function in the next generation, have not yet been evaluated.

The myogenic response is defined as increased or decreased vasoconstriction resulting from increased or decreased intraluminal pressure, respectively, and is essential to vascular tone development, peripheral resistance, and blood pressure regulation [19]. Not surprisingly, this physiological mechanism is important in vascular adaptations to pregnancy. Small radial uterine arteries in the rat [16, 20] exhibit increased myogenic responses during pregnancy, which likely are important for achieving appropriate fetoplacental circulation. We recently demonstrated that myogenic reactivity in radial uterine arteries from pregnant rats subjected to global diet restriction is greatly increased compared to control-fed (C) pregnant rats. This impaired pregnancy adaptation may lead to poor uteroplacental perfusion and reduced fetal weights [16]. Whether myogenic responses are similarly impaired in vessels from pregnant offspring of these same DR dams is unknown.

Cardiovascular adaptations to pregnancy include generalized vasodilation through enhanced nitric oxide and prostacyclin production [21]. Deficiencies in the nitric oxide pathway in both mesenteric [17] and uterine [15] arteries have been shown in animal models of maternal undernutrition. Although myogenic constriction occurs through a stretch-activated mechanism operating in the vascular smooth muscle, this response also has been shown in a number of vascular beds to be modulated by endothelial-derived factors, including nitric oxide and prostaglandins [19, 22, 23], and this modulation may be altered in situations of vascular dysfunction [24]. Previously, we observed impaired nitric oxide modulation of myogenic responses in uterine arteries of DR pregnant rats [16].

The objectives of the present study were to examine pregnancy outcome and myogenic responses in both uterine and mesenteric circulations from pregnant offspring of C or DR rat dams. Throughout the present study, the term myogenic response refers to both the vascular smooth muscle response to increasing pressure and the intact endothelial modulation of that response. We hypothesized that myogenic responses in both vascular beds would be enhanced in the pregnant offspring from DR compared to C dams as a result of impaired vasodilatory pathways.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
The present study was approved by the University of Alberta Health Sciences Animal Policy and Welfare Committee and was in accordance with the Canadian Council on Animal Care.

Animal Model

Female Sprague-Dawley rats (age, 12 wk) were mated, and Day 0 of pregnancy was defined as the morning on which vaginal plugs were identified. At this time, rats were randomly placed on ad libitum (standard lab chow, n = 3) or diet restriction (globally restricted by 50% of the average daily maternal intake of offspring of C rat dams in early pregnancy, ~12 g/day of standard lab chow, n = 4) through to delivery. Values stated are mean ± SEM. No significant differences were observed in litter size (C, 14.0 ± 2.01 pups/litter, n = 3; DR, 13.0 ± 1.68 pups/litter, n = 4). Mother and pups were returned to standard lab chow postpartum. Pups were weighed at birth and then every 10 days thereafter until termination of the experiment. No significant differences were observed in sex ratio between groups (data not shown). The first six female and two male pups were randomly chosen and placed back with their dams. To ensure equal feeding until weaning between groups, the remaining pups were culled. One to two female offspring from each dam were used in the following pregnancy studies, and the remainder of the offspring were used in nonpregnant and aging studies. No significant differences were found in results between offspring from each dam or in offspring between dams within a given treatment group.

Mature female offspring (age, 12 wk) were mated, and Day 0 of pregnancy was identified as previously defined. No significant differences were observed in mating success or pregnancy outcomes between groups. Rats were weighed before mating, at midpregnancy, and on the day they were killed (Day 20 of a 22-day gestation). Pregnant female offspring from both C (Coff; n = 6) and DR (DRoff; n = 6) dams were fed ad libitum throughout pregnancy.

Vascular responses in pregnant offspring were examined on Day 20 of a 22-day term pregnancy, which corresponds to a time of greatly elevated uterine blood flow in the rat [13].

Tissue Preparation

The rats were exsanguinated on reaching surgical plane anesthesia after an i.p. injection of Somnotol (60 mg/kg). The entire uterus was rapidly removed and placed in cold Dulbecco medium (Dulbecco modified Eagle medium base, 1 mM sodium pyruvate, 25 mM sodium bicarbonate, 5 mM Hepes, and 5 mM glucose). This medium ensured consistent viability of dissected uterine and mesenteric vessels [25]. Litter size of each dam was determined, and for consistency, the first three or four fetoplacental units from the cervical end of the right uterine horn were immediately removed. Fetal weights and corresponding placental weights were determined after separation of the placenta and removal of the placental membranes and excess liquid.

Uterine arteries were carefully dissected from a similar area of the radial uterine arterial tree from the right horn in each animal, and third-order mesenteric arteries were consistently dissected 5–10 cm distal to the pylorus in five of six Coff and in five of six DRoff. No overt differences were visible in either vascular bed between groups. After mounting on a pressure myograph system as previously described (Living Systems Instrumentation, Inc., Burlington, VT) [26], experiments were performed in Dulbecco medium at 37°C and pH 7.4. The vessels were depicted with a video camera, and internal diameter was measured using a video dimension analyzer (Living Systems).

Experimental Protocols

Arteries were equilibrated for 30 min at an intraluminal pressure of 60 mm Hg and prestretched by increasing intraluminal pressure from 60 to 75 mm Hg and immediately returning it to 60 mm Hg. The vessels were then allowed to equilibrate at 60 mm Hg for another 30 min. After the equilibration process, the intraluminal pressure was reduced to 20 mm Hg, and the vessels were further stabilized for 10 min. The pressure was then increased from 20 to 110 mm Hg in stepwise increments, and the lumen diameter measurement was taken 5–6 min after each pressure step.

This protocol for assessing myogenic response was repeated in the presence of the nitric oxide synthase (NOS) inhibitor, NG-nitro-L-arginine methyl ester (L-NAME; 100 µM), or the prostaglandin H synthase (PGHS) inhibitor, meclofenamate (1.0 µM). Results from the second pressure curves were independent of results obtained from the first curves, as suggested by the lack of significant differences observed between curves in Figure 3B or Figure 4.



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  		FIG. 3. Effect of L-NAME treatment on myogenic responses in radial uterine arteries from pregnant Coff (A) and DRoff (B). Myogenic responses were calculated as the percentage decrease in arterial diameter and reported as the mean ± SEM. *Significant differences between pregnant Coff vessels treated with and without L-NAME (P < 0.05), #significant differences from 60 mm Hg in L-NAME-treated vessels from Coff (P < 0.03)



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  		FIG. 4. Effect of meclofenamate treatment on myogenic responses in radial uterine arteries from pregnant Coff (A) and DRoff (B). Myogenic responses were calculated as the percentage decrease in arterial diameter and reported as the mean ± SEM. #Significant differences from 60 mm Hg in untreated vessels from pregnant DRoff (P < 0.03)

For the final passive curve, the vessels were incubated for 20 min in EGTA-Ca2+-free PSS (142 mM NaCl, 4.7 mM KCl, 1.17 mM MgSO4, 1.18 mM KH2PO4, 10 mM Hepes, and 2 mM EGTA) and papaverine (0.1 mM; Sigma-Aldrich Canada (Oakville, Ontario, Canada)).

Calculations

The following formula was used to calculate percent myogenic responses at each pressure step: % myogenic response = (D1 – D2)/D1 x 100, where D1 is the lumen diameter in Ca2+-free medium and D2 is the lumen diameter in the presence of extracellular Ca2+.

Data Analysis

Data analysis to assess differences in the myogenic response curves was performed using two-way ANOVA with a Fisher Least Significant Difference post-hoc test for multiple comparisons at each pressure step between groups. To compare differences between groups in offspring birth weights, maternal weight gain, litter size, fetal weights, placental weights, and fetal:placental weight ratios, Student t-tests were used. Data are expressed as the mean ± SEM. Statistical significance was accepted at P < 0.05.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Our approach was to examine myogenic responses in the uterine vasculature, which is dramatically altered during pregnancy [27], and in the mesenteric vasculature, which greatly contributes to systemic vascular resistance [28], from pregnant female offspring of DR versus C dams. Birth weights of all first-generation offspring from DR compared to C dams were significantly reduced (DRoff, 5.51 ± 0.256 g, n = 4; Coff, 6.38 ± 0.076 g, n = 3, P < 0.05), suggesting that this model of intrauterine growth restriction was successful. A trend toward significant reduction in birth weights of the female offspring (Coff, 6.25 ± 0.073 g, n = 3; DRoff, 5.48 ± 0.279 g, n = 4; P = 0.081) was resolved by 10 days of age (Coff, 24.4 ± 1.20 g; DRoff, 23.3 ± 0.286 g), suggesting that catch-up growth had occurred in this short period of time.

Pregnancy of Female Offspring

Adult female offspring body weights before mating did not differ between groups (Coff, 318 ± 7.43 g, n = 6; DRoff, 314 ± 9.83 g, n = 6). Total average weight gain during pregnancy also was not different between groups (Coff, 153 ± 12.6 g, n = 6; DRoff, 142 ± 7.27 g, n = 6). No significant differences were observed in litter size or total fetal weights between Coff and DRoff (Fig. 1, A and B). Although placental weights in DRoff were significantly reduced compared to those in Coff (P = 0.025) (Fig. 1C), the fetal: placental weight ratios were not significantly different (Coff, 6.51 ± 0.378; DRoff, 7.04 ± 0.485).



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  		FIG. 1. Pregnancy data for Coff and DRoff. A) Litter size for Coff (n = 6) and DRoff (n = 6). B) Fetal weight (g) at Gestational Day 20 (of a 22-day gestation) for Coff (n = 21) and DRoff (n = 22). C) Placental weight (g) at Gestational Day 20 for Coff (n = 21) and DRoff (n = 22). Data are reported as the mean ± SEM. *P = 0.025

Myogenic Responses of Uterine and Mesenteric Arteries

All uterine arteries demonstrated basal myogenic tone at 60 mm Hg that was not significantly different from that at pressures less than 60 mm Hg (data not shown). Constriction in Coff arteries was not significantly changed by increasing pressure (Fig. 2A). However, myogenic responses in DRoff arteries were significantly enhanced at both 100 and 110 mm Hg compared to that at 60 mm Hg (P < 0.03) (Fig. 2A). This resulted in a significant increase in myogenic response at the highest pressure tested (110 mm Hg) in radial uterine arteries from DRoff compared to those from Coff (P = 0.039) (Fig. 2A). No significant difference was found in myogenic responses of mesenteric arteries between groups (Fig. 2B). Passive curves were not different in either uterine or mesenteric arteries (data not shown).



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  		FIG. 2. Myogenic responses in radial uterine (A) and mesenteric (B) arteries from pregnant Coff and DRoff. Myogenic responses were calculated as the percentage decrease in arterial diameter and reported as the mean ± SEM. *Significant differences between radial uterine vessels from pregnant Coff and DRoff (P = 0.039), #significant differences from 60 mm Hg in radial uterine vessels from pregnant DRoff (P < 0.03)

Lumen diameters of radial uterine arteries (Coff, 188 ± 21.5 µm, n = 6; DRoff, 136 ± 19.9 µm, n = 6) and mesenteric arteries (Coff, 186 ± 8.49 µm, n = 5; DRoff, 200 ± 13.5 µm, n = 5) were not significantly different between groups under Ca2+-free conditions at 20 mm Hg.

Inhibition of NOS or PGHS and Myogenic Response

To examine further the enhanced myogenic responses found in radial uterine arteries from DRoff, myogenic response curves were repeated in the presence of inhibitors for NOS or PGHS. Uterine arteries from Coff pretreated with L-NAME showed significantly increased constriction at all pressures greater than 60 mm Hg (P < 0.03) (Fig. 3A). This resulted in significantly enhanced myogenic responses at pressures greater than 80 mm Hg compared to those in untreated uterine arteries (P < 0.05) (Fig. 3A). In contrast, the myogenic responses of uterine arteries from DRoff pretreated with L-NAME were not significantly affected by increasing pressure and were not different from those of untreated uterine arteries (Fig. 3B).

Inhibition of PGHS did not alter myogenic responses in uterine arteries from either Coff (Fig. 4A) or DRoff (Fig. 4B) compared to untreated arteries or in response to increasing pressure in either group.


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
A number of studies have demonstrated that diet restriction during rat pregnancy can lead to vascular dysfunction in the adult offspring [4, 5, 7, 8]. These long-term effects in offspring exposed to an adverse in utero environment are attributed to "fetal programming." Fetal programming, however, may not be confined to the first generation [9– 12]. Thus, first-generation female offspring with altered vascular adaptations during their pregnancies could, potentially, affect or program their second-generation offspring. However, the mechanisms that contribute to transgenerational effects are not understood. Although some evidence exists for altered mesenteric vascular responses in first-generation pregnant female offspring of protein-restricted dams [18], to our knowledge the uterine vasculature, which is dramatically altered during pregnancy, has not yet been evaluated in these animal models. In the present study, we found that radial uterine, but not mesenteric, arteries of pregnant female offspring from dams that were globally diet restricted during pregnancy show an enhanced myogenic response. We further observed that this increase may be the result of impaired NOS-mediated responses in, specifically, the uterine vasculature. Unlike the reduced birth weights observed in neonatal first-generation female offspring, no effect on second-generation fetal weights or litter size was immediately apparent. It is interesting to note, however, that placental weights were significantly reduced in pregnant offspring from DR compared to C dams.

The majority of epidemiological studies link low birth weight to an increased risk of cardiovascular diseases, such as hypertension and coronary heart disease [1]. Similar to our previous findings [16], DRoff were significantly smaller at birth than Coff, and the uterine arteries from pregnant DRoff showed NOS dysfunction, potentially leading to an enhanced myogenic response. However, these vascular changes in the first-generation offspring did not appear to affect the second-generation litter size or fetal weights. Because considerable fetal growth occurs during the last 2 days in utero [13], significant differences in birth weight among groups might become evident. However, a number of studies have demonstrated that development in an adverse in utero situation may not necessarily lead to impaired fetal growth based on weight but still result in detrimental effects on the cardiovascular and endocrine systems [8, 18]. Thus, although the fetal weights of the second-generation offspring were not significantly different among groups, altered vascular function may occur later in life. Additionally, fetal or birth weights may not be the only measure of altered intrauterine development, because birth length also may be associated with adult cardiovascular risk [29].

In the present study, although litter size and fetal weights from the second generation were not different between groups, placental weights were significantly reduced in DRoff. In our previous study [16], placental weights of the original DR dams also were significantly reduced compared to those from C dams (DR, 0.444 ± 0.030 g; C, 0.618 ± 0.043 g; P = 0.007). The reduction in placental size was modest in the present study, but this is only a very crude measure of placental function. In fact, the impairment in uterine artery function may have altered placental development in a way that cannot be measured by weight alone but still results in impaired fetal development [30]. Interestingly, a smaller placenta may reduce protection of the fetus from exposure to maternal glucocorticoids, which can alter fetal neuroendocrine function, leading to long-term consequences in adult life [11].

The enhanced myogenic responses observed in uterine arteries from pregnant DRoff compared to Coff are unlikely to result from differences in uterine blood supply given that both litter and fetal sizes were comparable between groups. Additionally, no differences were evident in either the uterine or mesenteric vasculature between groups that could account for the observed functional differences. Although the normal physiological pressures in radial uterine arteries during pregnancy are lower than the pressures at which we see differences in the myogenic response [31], the point of the present experiments was to compare the ability of vessels to undergo myogenic constriction at higher-than-normal pressures, as examined previously in uterine arteries [20], both proximal and distal, from the placenta [32].

The term myogenic response as used in the present study includes the stretch-activated vascular smooth muscle response to increasing pressure along with endothelial-derived modulation of that response [19, 24]. Functional inhibition of the NOS pathway significantly enhanced myogenic reactivity in the uterine arteries from pregnant Coff, confirming a vasodilator role for NOS in this vascular bed during pregnancy [33–35]. Conversely, NOS inhibition did not alter myogenic reactivity in uterine arteries from pregnant DRoff. Dysfunctional nitric oxide modulation of myogenic responses in the uterine vasculature could lead to increased vascular tone and reduced blood flow, which are characteristics of hypertension and preeclampsia. In our previous study [16], the NOS pathway was impaired in radial uterine arteries from DR dams, which may have contributed to the enhanced myogenic responses that were found. Thus, the offspring from these DR dams, which were growth restricted in utero, probably were predisposed to develop similar dysfunctional pregnancy-related vascular adaptations in uterine arteries, which resulted in enhanced myogenic reactivity.

Pregnant offspring from either C or DR dams do not show significant changes in the myogenic response in the presence of the PGHS inhibitor, meclofenamate. Our previous study [16] examining myogenic responses in the original treated dams also showed no involvement of PGHS in uterine artery myogenic responses. This result is in agreement with those of previous studies, which failed to show a dilatory role for prostanoids in pregnancy [36, 37]. The discrepancies between these studies and those showing involvement of PGHS-mediated vasorelaxation during pregnancy [35, 38] may be attributable to differences in either the vascular bed that was studied or the experimental protocol by which the involvement of PGHS products was examined. To our knowledge, the role of prostaglandins in modulation of myogenic responses in the uterine vasculature specifically has not been examined before the present study, and this may represent a distinct situation from those studies done in other vascular beds and those studies that examined the vasodilatory properties of prostanoids after preconstriction [35, 38]. Because meclofenamate can inhibit production of both vasodilators and vasoconstrictors through the PGHS pathway, the lack of significant modulation of myogenic responses suggests that either PGHS is not involved in this response or the inhibitor is blocking both a vasodilator and a vasoconstrictor such that the resultant response is a balance showing no overall change. The relative functional roles for PGHS-mediated vasoconstrictors versus vasodilators are being examined in a follow-up study using specific inhibitors of the PGHS-1 and PGHS-2 enzymes.

The vascular endothelium through which both the NOS and PGHS pathways can operate is important in the control of vascular tone and plays a critical role in the regulation of peripheral vascular resistance during pregnancy [38]. Endothelial dysfunction has been shown in growth-restricted human adults [39] and children [40] in addition to the offspring of DR rats [5, 7, 8]. Additionally, reduced activity of endothelial NOS and, perhaps, nitric oxide bioavailability along with impaired vascular function in offspring from DR dams has been demonstrated [5, 41]. Our previous studies showed that endothelial removal from uterine arteries of pregnant mice resulted in a comparable increase in myogenic responses to that found by NOS inhibition [42]. Therefore, we speculate that impaired endothelial function causes a relative deficiency of nitric oxide-mediated vasodilation during pregnancy and manifests as increased myogenic reactivity in the offspring of DR rat dams. Additional experiments involving an extended generational study will define further the role of the endothelium.

Even at 20 mm Hg, all uterine vessels have an initial vascular tone. A significant increase in this basal tone occurs in Coff at pressures greater than 60 mm Hg, but only in the presence of the NOS inhibitor. Interestingly, uterine vessels from DRoff showed increased myogenic constriction at both 100 and 110 mm Hg compared to 60 mm Hg, with no further increase in the presence of the NOS inhibitor, suggesting impairment of NOS at these pressures. However, because no increase was observed in myogenic responses in DRoff compared to Coff at the lower pressures at which NOS was active in Coff and no apparent effect by PGHS-mediated vasodilators was seen, we propose the existence of a compensatory vasorelaxation in DRoff, possibly mediated through endothelial hyperpolarizing factor [43].

In the present study, the pregnant DRoff showed increased myogenic responses in uterine but, interestingly, not in mesenteric arteries. This appears to be in contrast to the results in studies showing impaired vasorelaxation of preconstricted mesenteric arteries in both pregnant [18] and nonpregnant [7] female offspring from protein-restricted dams. Torrens et al. [18] suggest that the impaired vascular function in pregnant offspring may result from nitric oxide dysfunction. Different measures of vascular function (i.e., relaxation of preconstricted arteries compared to myogenic responses) may account for this discrepancy. Myogenic responses in the mesenteric vessels, the levels of which are considerably less than those found in uterine vessels, possibly were not altered in DRoff because of a functional redundancy in the vasorelaxation pathways. One study found that in an endothelial NOS-knockout mouse, an endothelial-derived hyperpolarizing factor appears to take over modulation of myogenic responses in mesenteric arteries [43]. However, we did not see impairment in either the nitric oxide or prostaglandin pathways in myogenic responses of mesenteric arteries from DRoff compared to Coff (data not shown), suggesting that compensatory vasodilatory pathways are not necessary for maintaining unaltered myogenic responses in this vascular bed.

In summary, the present study has shown that reduced maternal diet during pregnancy not only impairs uterine vascular function in the treated dams and reduced offspring birth weights but also specifically impairs uterine vascular function in their pregnant adult female offspring. These results suggest a mechanism whereby fetal programming may reach through to the next generation.


   FOOTNOTES
 
1 Supported by Canadian Institute of Health Research (CIHR). D.G.H. is a postdoctoral fellow supported jointly by Heart and Stroke Foundation of Canada and CIHR. S.V. is funded by through a Wyeth-Ayerst Fellowship Award and University of Alberta Perinatal Research Centre. P.N.B. is supported by Tommys: The Baby Charity. S.T.D. is a Canada Research Chair in Women's Cardiovascular Health and a Senior Scholar of the Alberta Heritage Foundation for Medical Research. Back

2 Correspondence: Sandra T. Davidge, Perinatal Research Centre, 220 Heritage Medical Research Centre, University of Alberta, Edmonton, AB T6G 2S2, Canada. FAX 780 492 1308; sandra.davidge{at}ualberta.ca Back

3 D.G.H. and S.V. contributed equally to this work Back

Received: 27 August 2004.

First decision: 29 September 2004.

Accepted: 7 December 2004.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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