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RESEARCH |
Laboratoire de Recherche Fondamentale en Obstétrique, Centre de Recherche, Département d’Obstétrique et Gynécologie, Hôpital Sainte-Justine, Université de Montréal, 175 Ch. Côte Sainte-Catherine, Montréal, Québec H3T 1C5, Canada
Correspondence should be addressed to J St-Louis; Email: jean.st-louis{at}umontreal.ca
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Abstract |
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Introduction |
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During pregnancy, the uterine circulation is subjected to substantial structural and functional changes to meet the growing needs of the fetus(es). These phenomena have been reviewed with special emphasis on pregnant sheep (Rosenfeld 2001). Several studies have shown that the uterine blood vessels enlarge in size via both hypertrophic and hyperplastic mechanisms (Osol & Cipolla 1993a, Cipolla & Osol 1994, Cipolla et al. 2000) and that a major part of these changes takes place during the last week of gestation in rats (St-Louis et al. 1997). Moreover, these important structural alterations are accompanied by functional modulations of vascular reactivity (Osol & Cipolla 1993b, D’Angelo & Osol 1994, Ni et al. 1997, St-Louis et al. 1997, 2001, Zwart et al. 1998). For instance, the uterine arterial effects of vasoconstrictor agonists like AngII and 
-adrenomimetics, acting on G protein-coupled receptors, are much stronger at term pregnancy (D’Angelo & Osol 1994, St-Louis et al. 1997). We have reported that losartan, an AngII (AT1-type) receptor blocker, has much weaker effects in the uterine arteries of term pregnant and early postpartum compared with non-pregnant rats (St-Louis et al. 2001). This result indicates that pregnancy is associated with significant regulation of AngII receptor subtypes (AT1/AT2) relative to each other. Studies in sheep have revealed predominant binding of AngII to the AT2 receptor subtype in uterine artery smooth muscle (Cox et al. 1996a,b, Burrell & Lumbers 1997). Moreover, it has been reported that AT1 receptor subtype expression is heightened in the uterine artery endothelium of pregnant sheep (Bird et al. 1997). Such data are not available for rats, presumably because of the very low expression of AngII receptors in the uterine vasculature of this species.
In the present study, we modified salt intake during gestation to investigate the impact of RAAS modulation on the structural and functional characteristics of uterine arcuate arteries in rats. Indeed, sodium restriction has been found to obliterate the increase of blood volume in normal gestation (Roy-Clavel et al. 1999). As heightened circulatory volume is required to augment uterine perfusion during gestation, it was suspected that any perturbation of the former should have a strong impact on both the remodeling and the function of the uterine vasculature. We hypothesized that increased and decreased RAAS activation during gestation, through reciprocal alterations of sodium intake, will modify remodeling and myotropic responses of the uterine arterial system associated with pregnancy.
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Materials and Methods |
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Myotropic responses of the uterine arcuate arteries
The uterine horn and attached vasculature were rapidly removed and placed in cold oxygenated Krebs bicarbonate solution (KBS). An arcuate artery, at the midpoint of the uterine arcade, was cleaned of adhering tissues under a stereomicroscope. A section of about 1.5 mm was isolated, and two tungsten wires (20 µm diameter) were inserted into the lumen to secure the vessel to myograph supports (Kent Scientific, Litchfield, CT, USA) (St-Louis et al. 1997, 2001). One support was attached to a strain gauge force transducer (TRN 001; Kent Scientific) and the other to a micrometer. Force was recorded on a computer with the Workbench data acquisition package (Kent Scientific). The arcuate artery segment was bathed in 7 ml circulating KBS (in mmol/l: NaCl, 118; KCl, 4.65; NaHCO3, 25; CaCl2, 2.5; MgSO4, 1.18; KH2PO4, 1.18; and dextrose, 5.5), and bubbled with 95% O2 and 5% CO2; pH was 7.4. A passive length–tension relationship was generated by increasing the distance (in steps of 25 µm) between the myograph supports. The results were fitted (Prism; GraphPad, San Diego, CA, USA) to an exponential equation that intercepted the theoretical straight line of Laplace (for a pressure of 50 mmHg) at diameter L50 (L50; the diameter or internal circumference that the arterial segment would have at a transmural pressure of 50 mm Hg) used as passive tension (Mulvany & Halpern 1977, St-Louis et al. 1997, 2001).
After equilibration (30 min) at this tension, the vessels were challenged with 10–6 mol/l phenylephrine (Phe) and, on top of this response, with 10–4 mol/l carbachol to verify the presence of a functional endothelium. The rest of the experiment was performed with 10–4 mol/l N
-nitro-L-arginine methyl ester (L-NAME). After returning to baseline, two cumulative concentration–response curves to AngII (10–11 to 10–6 mol/l) were obtained, first under basal conditions and then after 90-min re-equilibration, under AT1 receptor blockade with losartan (10–7 mol/l, 10-min preincubation). This protocol was not associated with tachyphylaxis to the pressor peptide (St-Louis et al. 2001).
Data analysis
Concentration–response curves were analysed by computer fitting to a four-parameter logistic equation (Prism) to evaluate the the AngII concentration required to produce 50% of the maximum response (EC50) and the maximum response (EMax). The potency of the AT1 receptor antagonist losartan was measured by the method of Furchgott (1978) and expressed as the apparent dissociation constant KA (–log KA(app)) (St-Louis et al. 2001). Sensitivity (pD2; the negative logarithm of AngII concentration that produce 50% maximum response (EC50)) and EMax were compared by one-way ANOVA, followed by Bonferroni comparison for selected pairs of groups with non-pregnant and pregnant animals on the control diet serving as controls. Values were considered to be statistically significant when they reached P < 0.05. The data are reported as means±S.E.M. along with the curve best fitted to the data points.
Drugs and chemicals
All salts employed in these experiments were of analytical grade and obtained from Fisher Scientific (Montréal, QC, Canada). AngII (Asp1, Ile5-AngII) was purchased from Peninsula Laboratories (Belmont, CA, USA), phenyl-ephrine hydrochloride and carbachol hydrochloride from Sigma Chemical Co. (St Louis, MO, USA) and L-NAME from Research Biochemical International (Natick, MA, USA). Losartan was generously provided by Merck Frosst (Montréal, QC, Canada).
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Figure 1A
shows the length–tension relationship of the uterine arteries of non-pregnant and pregnant rats on the control and low-sodium diets. Pregnancy was associated with increased wall tension for any given relative stretch (L/L50) of arterial segment (the two solid lines). This can be explained by parameters of the exponential curves (Y = Aeßx), in which A is the wall tension at L50 and ß represents the proportional changes in vessel circumference modifying wall tension. Pregnancy significantly heightened arterial wall tension at any given relative stretch (transmural pressure). This could be the consequence of the significant remodeling that affects the wall of uterine vessels during pregnancy (changes in diameter). On low-sodium intake, the increase in wall tension to relative stretch of the arcuate arteries was markedly increased (the two broken lines). Indeed, reduced sodium intake significantly augmented the exponential ß parameter (slope) of the equation (non-pregnant, from 3.36 ± 0.43 to 5.02 ± 0.37 and pregnant, from 3.02 ± 0.20 to 4.03 ± 0.23; both P < 0.05, n = 10 in all groups). Such an effect will produce steeper increments in wall tension with growing internal circumference of the arterial segment. This occurred in arteries of both non-pregnant and pregnant rats, although it was of significantly lower magnitude in the arteries of pregnant animals.
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illustrates the length–tension relationship in the arcuate artery of non-pregnant and pregnant rats on control and high-sodium (two groups) intake. Sodium supplementation slightly modified the increased tension to relative stretch of these vessels, resulting in reductions of the ß parameter of the exponential relationship (non-pregnant, from 4.48 ± 0.28 (n = 14) to 2.95 ± 0.33 (n = 13) (P < 0.05) and 3.89 ± 0.42 (n = 12) (n.s.) and pregnant, from 4.44 ± 0.20 (n = 12) to 3.09 ± 0.17 (n = 13) (P < 0.05) and 3.91 ± 0.15 (n = 17) (n.s.), for 0.9% and 1.8% supplementation respectively). This demonstrated that, opposite to the low-sodium diet, the arteries of rats on sodium supplements showed decreased tension responses to relative changes in circumferential stretch (smaller exponential slope) compared with normally fed rats.
Responses to AngII
Figure 2A depicts the myotropic responses to AngII in uterine arcuate arteries of non-pregnant and pregnant rats on the control diet, in the absence and presence of the AT1 receptor antagonist losartan (100 nmol/l). In the vessels of pregnant compared with non-pregnant animals, the effects of AngII were markedly increased (Table 1; EMax, control groups). Sensitivity of the arcuate artery to AngII (pD2) was not significantly changed by gestation. In both conditions, concentration–response curves to AngII were markedly right-shifted in the presence of 100 nmol/l losartan (broken lines in Fig. 2A), significantly more in non-pregnant than in pregnant rats. Indeed, fitting these curves to the sigmoid equation was compatible with competitive antagonism for losartan, since the same maximum responses could be fitted in both the presence and absence of the antagonist with a slope not different from unity. This allowed the calculation of an apparent dissociation constant (–log KA(app)) for losartan (Furchgott 1978). Such a calculation indicated that sensitivity to losartan was significantly decreased in arteries of pregnant compared with non-pregnant rats (Table 1). The initial response to Phe (1.0 µmol/l) was increased in arteries of pregnant rats, as was the AngII maximum response.
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. Opposite results were obtained, since the arteries of non-pregnant animals presented stronger responses to AngII than those of pregnant rats (EMax; Table 1). AngII responses of the arteries of non-pregnant rats on the low-sodium diet were not different from pregnant rats on the control diet, whereas the arteries of pregnant rats on the low-sodium diet showed similar responses to AngII as non-pregnant rats on the control diet (Fig. 2A and B). Sensitivity to AngII was decreased in the arcuate arteries of pregnant animals under low sodium (Table 1), as illustrated by the rightward shift of the concentration–response curve in Fig. 2B. Again, losartan produced strong inhibition of AngII responses and the apparent affinity of the AT1 receptor antagonist was reduced in the arcuate arteries of pregnant compared with non-pregnant rats. The response to Phe was increased in the arteries of non-pregnant rats on the low-sodium diet, but no change was observed in the pregnant animals (Table 1). As the low-sodium diet during the third (last) week of gestation elicited a marked reduction of blood volume expansion (Roy-Clavel et al. 1999), we attempted some plasma volume reduction with subcutaneous injections of PEG, compared with saline, during the same period of pregnancy. As expected, this manoeuvre evoked a pronounced increase of the RAAS, as demonstrated by elevation of PRA from 8.8 ± 1.1 to 28 ± 5 pmol AngI/ml per h, and aldosterone from 1.3 ± 0.3 to 16 ± 3 nmol/ml (n = 7 and 9 respectively). Hematocrit was also augmented (from 33 ± 1.3 to 35 ± 1%; P < 0.05) upon PEG treatment, indicating significant hemoconcentration, while plasma sodium fell from 136 ± 1 to 124 ± 2 mmol/l. These data resemble those obtained with the low-sodium diet (Roy-Clavel et al. 1999).
The uterine arcuate arteries of PEG- and saline-treated rats had a similar diameter (270 ± 16 (n = 7) vs 290 ± 16 µm (n = 9)). Similarly, the length–tension relationship in uterine arcuate arteries was not affected by PEG (data not shown). Figure 2C reveals that PEG significantly reduced the maximum response to AngII, similarly to low-sodium intake. Sensitivity to AngII and losartan was not affected by PEG in pregnant rats, results that were somewhat different from findings in pregnant rats on normal and low-sodium intakes. The contractile effect of Phe (1.0 µmol/l) was reduced to a similar level as in rats on the low-sodium diet by PEG treatment (Table 1).
Reactivity to AngII, measured in the arteries of rats given sodium supplements as 0.9 or 1.8% saline for beverage, is shown in Fig. 3. Compared with the control diet (Fig. 2A), the two sodium supplements did not modify the maximum response of the uterine arcuate arteries to AngII in non-pregnant rats (Table 1). In pregnant rats, the increased response to AngII was blunted by sodium supplements, although this was significant only in the 0.9% saline group (Table 1). Sensitivity to AngII was not different in the four groups of animals (non-pregnant and pregnant on both supplements) from those on normal sodium intake. The apparent potency of inhibition of the AngII response by losartan was decreased in the arteries of non-pregnant rats on 0.9% NaCl supplementation and also in tissues of pregnant rats. 1.8% NaCl supplemention did not affect apparent sensitivity to losartan in both groups of animals (Table 1). The response of the uterine arcuate arteries to Phe was significantly modified (decreased) only in the arteries of non-pregnant rats on 0.9% NaCl (Table 1).
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Discussion |
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During pregnancy, the uterine circulation has to adapt to the growing nutritional needs of the fetus(es). In fact, blood flow to the reproductive organs is enhanced by 23-fold during gestation in the rat through more than 75% increased diameter of the parametrial (main) and segmental (arcuate) arteries (Bruce 1976). This fits with our present and previous (St-Louis et al. 1997, 2001) observations as well as reports in the literature (Annibale et al. 1990, D’Angelo & Osol 1993, Osol & Cipolla 1993a, Cipolla & Osol 1994, Dalle-Lucca et al. 2000). Modified sodium intake did not have any effect on uterine artery size in non-pregnant rats, but blunted the increase in diameter of these arteries during gestation. As observed previously, we recorded heightened passive tension to stretch of the uterine arcuate arteries of pregnant compared with non-pregnant rats (St-Louis et al. 1997, 2001), similar to the results presented in Fig. 1. Such findings were also made in pregnant sheep uterine arteries (Annibale et al. 1990). However, the current data suggest that this is probably the consequence of the arterial wall remodeling associated with pregnancy (Cipolla & Osol 1994). Indeed, pregnancy did not much affect the exponential increase in tension upon stretching, but markedly augmented resting wall tension at normalized distension (Mulvany & Halpern 1977), an augmentation that is compatible with enlarged lumen diameter, without change in wall thickness (Annibale et al. 1990, Osol & Cipolla 1993a, D’Angelo & Osol 1994, St-Louis et al. 1997). On the other hand, the low-sodium diet enhanced the exponential increase in tension upon circumferential stretching of the arterial segment, whereas 0.9% sodium supplementation decreased this parameter. These effects were of a similar magnitude in the arteries of non-pregnant and pregnant rats. This appears to be an original observation. Nevertheless, our findings reveal that decreased and increased sodium intakes have opposite effects on the mechanical properties of uterine arcuate arteries. The impact of these opposite effects of decreased and increased sodium intake on uterine blood flow during pregnancy remains to be investigated, but reported observations suggest that the enhanced stiffness and/or reduced diameter of the uterine arcuate artery on a low-sodium diet (present study) are associated with intrauterine growth restriction of the pups (Roy-Clavel et al. 1999).
It is well recognized that gestation is associated with increased reactivity of the uterine arterial system to vasoconstrictors (Annibale et al. 1989, D’Angelo & Osol 1993, St-Louis et al. 1997, Zwart et al. 1998, Dalle-Lucca et al. 2000). Treatment with the low-sodium diet and sodium supplements also had significant effects on the reactivity of the uterine artery to AngII that are not similar in pregnant and non-pregnant rats. In the latter, the low-sodium diet markedly increased uterine vascular responses to the peptide, whereas sodium supplementation (1.8%) was associated with a slight decrease of maximum responses to AngII. In pregnant animals, the enhanced contractile effect of the peptide on the uterine arcuate artery was completely obliterated (or reversed) by the low-sodium diet. Similar results were obtained with the initial response to Phe (1.0 µmol/l). Sodium supplementation also induced similar decreases in the responses to AngII in uterine arteries compared with normally fed pregnant rats. It is suggested that sodium homeostasis is easily disturbed during pregnancy, while non-pregnant animal are hardly affected.
Similar modifications of salt intake resulted in very different responses of the rat aorta. Indeed, reduction of sodium intake (chow containing 0.2% instead of 1% NaCl) increased the reactivity of thoracic aorta strips to Phe and KCl that was only significant in pregnant rats and in a model of reduced uterine perfusion pressure (RUPP) during gestation (Giardina et al. 2002). Their results in non-pregnant rats fit with the large increase in the maximum response to AngII that we obtained in uterine arteries whereas, in pregnant animals, it appears that the decrease under low-sodium is specific for either uterine arteries or AngII responses. Specificity to the uterine vasculature seems to be appropriate since the initial responses to Phe (1.0 µmol/l) were similarly affected by low-sodium intake (Table 1).
In similar experiments with increased sodium intake (8% vs 1% NaCl), heightened responses to Phe in the aorta of pregnant rats, both normal and RUPP, were observed (Barron et al. 2001). In our sodium-supplemented groups, the aortic rings of non-pregnant rats manifested decreased maximal responses to Phe and arginine-vasopressin, but not to KCl. However, the reduced maximal responses to these agents observed in the aorta of pregnant compared with non-pregnant rats were reversed by sodium supplementation (Auger et al. 2004). In the present results, reduced responses to AngII in uterine arcuate arteries were obtained with both sodium supplements in pregnant rats and with 1.8% NaCl in non-pregnant animals. This closely resembles our data in the aorta (Auger et al. 2004) more than the findings of Barron et al.(2001).
Concerning sensitivity to AngII, our results were complicated by the presence of AT2 receptor subtypes in these blood vessels (Zwart et al. 1998, St-Louis et al. 2001, Hannan et al. 2003). Indeed, it has been shown that blockade of AT2 with PD 123319, its specific ligand, potentiated the contractile effects of AngII on uterine arteries (Zwart et al. 1998, St-Louis et al. 2001). This increased response to AngII was attributed to some unidentified inhibitory action of AT2 stimulation on the responses mediated by AT1 stimulation. Sensitivity of the arcuate artery to AngII was not significantly modified by different sodium intakes compared with the control diet in non-pregnant animals. This also holds true for pregnant animals, except on the low-sodium diet when significantly decreased sensitivity to AngII was observed. The heightened response to AngII was attributed to uncoupling of AT2 inhibition, consequent to the reduced density of this receptor subtype (Zwart et al. 1998, St-Louis et al. 2001). As reported previously, sensitivity of the uterine arcuate artery to losartan was significantly diminished by pregnancy despite the large increase of the maximum response (St-Louis et al. 2001). The low-sodium diet in pregnant rats significantly enhanced the sensitivity of the arcuate arteries to losartan, but not in non-pregnant animals.
While the low-sodium diet had similar effects on sensitivity of the uterine arteries to losartan in both groups of rats, sodium supplementation provided more complex results. The 0.9% sodium supplement significantly decreased sensitivity to losartan in the arteries of non-pregnant animals and increased it in pregnant rats. In contrast, the 1.8% supplement did not show any significant effects on this parameter compared with rats in the same condition on the control diet. This suggests that the 1.8% sodium supplement restored sensitivity to losartan to the level obtained with the regular diet, but more work is needed to explain such discrepancies.
In conclusion, modifications of sodium intake have significant effects on the mechanical properties of uterine arcuate arteries that are similar in magnitude in pregnant and non-pregnant rats, but which go in opposite directions with reduced and increased sodium intakes. This indicates that perturbations of sodium balance or of the RAAS during pregnancy interfere with the uterine vascular remodeling associated with the condition. In contrast, altered sodium intake has significant effects on the reactivity of these arteries to AngII that are very different in pregnant and non-pregnant rats. The involvement of AT1 receptors in these changes appears to vary according to pregnancy and sodium intake, suggesting, as postulated (St-Louis et al. 2001), the regulation of AngII receptor subtypes that so far has remained undocumented. The results presented here are indicative of a modified influence or role of the RAAS during gestation. For instance, during low sodium diet and PEG treatment in pregnant animals, increased RAAS, probably as a result of reduced plasma volume (hematocrit elevation), impedes remodeling of the uterine arterial system, modifying the size and reactivity of the uterine arcuate artery. In the increased sodium intake model, only the reduction of plasma volume, probably caused by the need to excrete more water and sodium, contributes to the smaller attenuation of remodeling with much less impact on size and reactivity of the uterine arcuate artery. However, the present data clearly demontrate that sodium handling is more critical during pregnancy.
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Acknowledgements |
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Footnotes |
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionAcknowledgementsReferences |
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Annibale DJ, Rosenfeld CR & Kamm KE 1989 Alterations in vascular smooth muscle contractility during ovine pregnancy. American Journal of Physiology. Heart and Circulation Physiology 256 H1282–H1288.
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