Published online before print May 7, 2007, doi: 10.1161/HYPERTENSIONAHA.106.085035
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(Hypertension. 2007;50:96.)
© 2007 American Heart Association, Inc.
Original Articles |
Paradoxical Role of Angiotensin II Type 2 Receptors in Resistance Arteries of Old Rats
From the Centre National de la Recherche Scientifique Unité Mixte de Recherche (CNRS UMR) 6214 (A.B., O.D., K.R., R.A., L.L., D.H.), Institut National de la Santé Et de la Recherche Médicale UMR (INSERM UMR) 771 (A.B., O.D., K.R., R.A., L.L., D.H.), Université d’Angers; and Centre Hospitalier Universitaire d’Angers (F.P., C.B.), Department of Cardiac Surgery and Unité Propre de Recherche de l’Enseignement Supérieur-Equipe Associée 3860, Angers, France.
Correspondence to Daniel Henrion, Department of Neurovascular Integrated Biology, UMR CNRS 6214, INSERM 771, Faculté de Médecine, 49045 Angers, France. E-mail daniel.henrion{at}univ-angers.fr
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Abstract |
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The role of angiotensin II type 2 receptors (AT2Rs) remains a matter of controversy. Its vasodilatory and antitrophic properties are well accepted. Nevertheless, in hypertensive rats, AT2R stimulation induces a vasoconstriction counteracting flow-mediated dilation (FMD). This contraction is reversed by hydralazine. Because FMD is also decreased in aging, another risk factor for cardiovascular diseases, we hypothesized that AT2R function might be altered in old-rat resistance arteries. Mesenteric resistance arteries (250 µm in diameter) were isolated from old (24 months) and control (4 months) rats receiving hydralazine (16 mg/kg per day; 2 weeks) or water. FMD, NO-mediated dilation, and endothelial NO synthase expression were lower in old versus control rats. AT2R blockade improved FMD in old rats, suggesting that AT2R stimulation produced vasoconstriction. AT2R expression was higher in old rats and mainly located in the smooth muscle layer. In old rats, AT2R stimulation induced endothelium-independent contraction, which was suppressed by the antioxidant Tempol. Reactive oxygen species level was higher in old-rat arteries than in controls. Hydralazine improved FMD and NO-dependent dilation in old rats without change in AT2R expression and location. In old rats treated with hydralazine, reactive oxygen species level was reduced in endothelial and smooth muscle cells, and AT2R-dependent contraction was abolished. Thus, AT2R stimulation induced vasoconstriction through activation of reactive oxygen species production, contributing to decrease FMD in old-rat resistance arteries. Hydralazine suppressed AT2R-dependent reactive oxygen species production and AT2R-dependent contraction, improving FMD. Importantly, endothelial alterations in aging were reversible. These findings are important to consider in the choice of vasoactive drugs in aging.
Key Words: aging • endothelium • microcirculation • angiotensin II receptors • NO • oxidative stress • vasodilator agents
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Introduction |
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Resistance arteries play a key role in vascular homeostasis. They possess a basal vasoconstrictor tone1,2 counteracted in part by flow (shear stress)-mediated dilation (FMD). Their tone is modified in hypertension, ischemic diseases, myocardial infarction, or diabetes, with situations being more frequent in aging.3–5 In aging, large arteries develop calcification and become less compliant.6 By contrast, resistance arteries do not develop calcification or stiffening in old subjects; nevertheless, the microvascular network becomes less efficient.1 Indeed, aging reduces the ability to increase blood flow to skeletal muscle, as shown in rats7 and humans,8 because of endothelial dysfunction.3 Endothelium-dependent contraction is increased in aging in parallel with a decreased endothelial capacity to produce vasodilator agents.9 In humans, FMD, assessed by forearm blood flow measurement after reactive hyperemia, is lowered.10–12
We have shown previously that angiotensin II type 2 receptor (AT2R) is involved in FMD in normotensive rat resistance arteries,13 whereas in hypertensive animals, FMD is counteracted by angiotensin II type 1 receptor (AT1R)– and AT2R-induced vasoconstriction.2,14 Because hypertension is often presented as a premature vascular aging, we tested the hypothesis that, in aging, AT2R receptor function might also be altered in resistance arteries. Thus, we determined the involvement of AT2R-dependent tone in FMD and determined the pathway stimulated after stimulation of AT2R in resistance arteries isolated from old rats. In addition, because we have shown previously that a chronic treatment with hydralazine reverses AT2R-dependent contraction into dilation in hypertensive rats,2 we also tested the hypothesis that hydralazine might improve AT2R-dependent tone and/or FMD in old rats. We used a dose of hydralazine shown previously to improve mesenteric blood flow without changing systemic blood pressure.15
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Methods |
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Animals
Twelve old (24 months) and 12 young (4 months) male Wistar rats (Iffa-Credo) were treated for 2 weeks with hydralazine (16 mg/kg per day in drinking water)15 or tap water (control). They were then anesthetized with isoflurane. Arterial blood pressure was measured in the femoral artery. Their mesentery was then removed to isolate mesenteric resistance arteries (MRAs).
The procedure followed in the care and euthanasia of the study animals was in accordance with the European Community Standards on the Care and Use of Laboratory Animals (Ministère de l’Agriculture, France, authorization 6422). From each rat, several segments of mesenteric arteries were isolated for the following experiments.
Pressure and Flow-Dependent Tone in MRAs
From each rat, a segment of third-order MRA was cannulated and mounted in a video-monitored perfusion system, and myogenic tone was measured. FMD was then determined before and after NO synthesis or AT2R blockade. At the end of the experiment, passive diameter of the vessel, that is, in the absence of smooth muscle tone, was measured (see the online data supplement at http://hyper.ahajournals.org).
Vascular Response to Exogenous Angiotensin II in Isolated Mesenteric Arteries
Six segments of MRAs were used per rat (12 rats per group) to test the effect of endothelium removal, NO synthesis blockade with NG-nitro-L-arginine methyl ester (L-NAME; 100 µmol/L), cyclooxygenase blockade with indomethacin (10 µmol/L), bradykinin B2 receptor blockade with HOE 140 (10 µmol/L), AT2R blockade with PD 123319 (10 µmol/L), or reactive oxygen species (ROS) removal with the catalase mimetic Tempol (100 µmol/L) on AT2-dependent dilation or contraction (see the data supplement).
Western Blot Analysis of AT2Rs and Endothelial NO Synthase Expression and Immunohistological Analysis of AT2Rs
For details, see the online data supplement.
Detection of ROS Using Confocal Microscopy in Resistance Arteries
ROS detection was performed on transverse cross-sections 7-µm thick incubated with dihydroethydine, as described previously.16 Positive staining using confocal microscopy and image analysis was performed as described above.
Statistical Analysis
Results were expressed as mean±SEM. Significance of the differences between groups was determined by ANOVA: 2-factor ANOVA on the whole curve or 1-way ANOVA followed by a Bonferroni test. P<0.05 was considered to be significant.
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Results |
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AT2R blockade with PD123319 (10 µmol/L) significantly reduced FMD in young rats (Figure 1A) and significantly increased FMD in old rats (Figure 1B). In old rats, the effect of PD123319 on FMD was more pronounced in the range of low flow rates (until 21 µL/min; Figure 1B). After treatment with hydralazine in young rats, PD123319 also reduced FMD (Figure 1C). This effect of PD 123319 was not significant using a 2-factor ANOVA on the whole curve, but a significant effect was found for the flow range 15 to 30 µL/min when using a 1-way ANOVA followed by a Bonferroni test. In old rats treated with hydralazine, PD123319 had no significant effect on FMD (Figure 1D).
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Western blot analysis performed in MRA showed that AT2R expression was significantly higher in old versus young rats. Hydralazine had no significant effect on AT2R expression level in old rats but significantly increased AT2R expression in young rats (Figure 1E).
In MRAs, AT2R was visualized using confocal microscopy and fluorescent angiotensin II in the presence of candesartan. AT2Rs were present in both the endothelium and the tunica media in young and old rats. Nevertheless, in old rats, AT2R density in the endothelium was 3 times lower than in young rats (Figure 2). Hydralazine had no significant effect on AT2R location (Figure 2). Negative control (in the presence of PD 123319 or in the absence of fluorescent angiotensin II) showed the absence of labeling.
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Acute stimulation of AT2R with angiotensin II in the presence of candesartan induced dilation in young rats, which was not significantly affected by hydralazine (Figure 3A through 3E). Removal of the endothelium (Figure 3A) and NO synthesis blockade (L-NAME; Figure 3B) suppressed AT2R-dependent dilation in young rats, whereas the indomethacin did not affect AT2R-dependent dilation (Figure 3C). AT2R blockade with PD 123319 abolished the dilation (Figure 3D), and bradykinin B2 receptor blockade with HOE 140 (Figure 3E) significantly decreased AT2R-dependent dilation in young rats treated or not treated with hydralazine.
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In old rats, AT2R stimulation induced contraction (Figure 3A through 3E). In old rats treated with hydralazine, AT2R-dependent contraction was suppressed. Endothelium removal (Figure 3A), NO synthesis blockade (L-NAME; Figure 3B), cyclooxygenase blockade with indomethacin (Figure 3C), and bradykinin B2 receptor blockade with HOE 140 (Figure 3E) did not affect AT2R-dependent contraction (Figure 3A). AT2R blockade with PD 123319 abolished AT2R-induced contraction in old rats (Figure 3D).
Antioxidant treatment of the isolated MRA with Tempol did not affect AT2R-dependent dilation in young rats, but it suppressed AT2R-dependent contraction on old rats (Figure 4A). ROS were detected using dihydroethydine staining and confocal microscopy (Figure 4B). In old rats, ROS level was significantly higher in the endothelium and in the smooth muscle cell layer than in young animals (Figure 4C). Hydralazine had no significant effect on ROS production in young rat arteries. In old rats, hydralazine significantly reduced the ROS level in both endothelial and smooth muscle cells (Figure 4C).
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Discussion |
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This study identified a paradoxical role of the AT2R in resistance arteries isolated from old rats. Stimulation of AT2R by endogenous (in response to shear stress) or exogenous angiotensin II induced contraction through the production of ROS by smooth muscle cells in old rats. This effect contrasts with AT2R-dependent dilation in young rats. A treatment with hydralazine improved FMD in old rats through a strong reduction in ROS production.
Myogenic tone was lower in old versus young rats as shown previously in mesenteric and coronary arteries.17,18 Aging was also associated with a decreased FMD with a rightward shift of the flow rate response curve (lower sensitivity) and a decreased maximal response. This is in agreement with previous reports in large arteries,3,19 in rat soleus feed arteries,20 and in the human brachial circulation.11 In parallel, we found in old rats a decreased involvement of NO in FMD, suggesting a decreased endothelial NO synthase activity, as shown previously.20–22
The presence of AT2R in the adult vasculature is now well recognized, although its role remains a matter of controversy.23–25 Our previous works suggest that AT2R stimulation, which does not induce desensitization, might have a role in hypertensive patients treated with AT1R blockers.26 Indeed, AT1R blockers induce AT2R overexpression and increase circulating angiotensin II.25
We found that AT2R-dependent dilation in MRAs (young rats) depended on the presence of the endothelium and was inhibited by NO-synthesis blockade and bradykinin B2 receptor blockade, whereas cyclooxygenase inhibition with indomethacin did not affect the dilation. These findings are in agreement with our previous reports in the same arterial bed2,13,14,26 and in other arteries.25 The involvement of the bradykinin B2 receptor in AT2R-dependent dilation has been described in several vascular territories, including the mesentery,27 and in the renal circulation.28 Heterodimerization of bradykinin B2 receptor and AT2R might occur29 after AT2R stimulation to activate NO production in endothelial cells. This interaction between the 2 receptors might be efficient in the 2 directions, because bradykinin B2 receptor dilation involved in FMD is reduced by AT2R blockade in the mouse carotid artery.30 On the other hand, AT2R located on smooth muscle cells can downregulate Rho/Rho kinase activity, at least in conditions inducing AT2R upregulation, such as chronic AT1R blockade in hypertensive rats.31
A main new finding of the present study is that FMD was counteracted by AT2R-dependent contraction in old rats. This effect was mainly significant with low flow values. Stimulation of AT2R by exogenous angiotensin II also produced a vasoconstriction in old rats, which was not suppressed by endothelium removal. In old rats, AT2R expression was higher than in young animals, and AT2Rs were mainly located to the smooth muscle cells layer. Finally, AT2R-dependent contraction was suppressed by the antioxidant Tempol. Thus, in aging, AT2Rs located in the smooth muscle layer induced ROS-dependent contraction.
We have previously observed AT2R-induced contraction in spontaneously hypertensive rats, also in association with a preferential muscular location, although the expression level of AT2R is low in spontaneously hypertensive rats.2 In spontaneously hypertensive rats, AT2R function depends on blood pressure. AT2R-induced contraction occurs with high blood pressure and AT2R-induced dilation with normal blood pressure.2
In addition, AT2R-dependent contraction in old-rat resistance arteries was suppressed by the antioxidant Tempol, whereas it was unaffected by endothelium removal or indomethacin. Thus AT2R-dependent contraction was mediated by ROS. Angiotensin II–induced contraction through AT1R also involves ROS in pathological situations.32 Thus, AT2R in aging, at least in MRAs, might induce contraction through a similar mechanism. Aging was associated with a high basal ROS production in resistance arteries, as shown in other cell types.33 Further supporting the key role of ROS in AT2R-dependent contraction, we found that hydralazine, which reduced ROS level in arteries from old rats, also suppressed AT2R-induced contraction.
The probability of developing cardiovascular diseases requiring a treatment with AT1R blockers or angiotensin-converting enzyme inhibitors increases with age. AT1R blockers induce AT2R overexpression and increase circulating angiotensin II.25 Both effects should produce additional vasodilation and, thus, increase the protective effect of AT1R blockade. Nevertheless, this protective effect in patients treated with AT1R blockers may not occur in old patients, unless AT2R-dependent contraction is reversed by vasodilator treatments in aging as it is in hypertension.2 This is possible, because hydralazine suppressed AT2R-related contraction in the present study.
The beneficial effect of hydralazine on FMD in old rats is the second new finding of the present study. First, in hydralazine-treated old rats, FMD was restored to the control level in association with an increased NO-dependent tone. Second, hydralazine suppressed AT2R-dependent contraction in old rats. The possibility to restore FMD to control level in old rats is a key finding showing that, in resistance arteries, the alteration is not irreversible. We have shown previously that a chronic treatment with hydralazine improves FMD in association with outward hypertrophic remodeling because of increased mesenteric blood flow.15 This is associated with an increased endothelial NO synthase expression in arteries from hydralazine-treated rats.15
In old rats, outward remodeling also occurred (as shown by an increased passive arterial diameter) in hydralazine-treated rats. Nevertheless, endothelial NO synthase expression did not increase in old rats treated with hydralazine, although NO-dependent tone (efficacy of L-NAME) increased. In addition, in old rats treated with hydralazine, FMD was restored to control level, despite an absence of effect on endothelial NO synthase expression. Nevertheless, FMD was enhanced for 2 reasons: AT2R-induced contraction was suppressed, and NO-biodisponibility was enhanced, as visualized by an increased efficiency of L-NAME in blocking FMD in old-rat resistance arteries. In both cases, ROS production had a central role. First, AT2R-induced contraction depended on ROS production, and in hydralazine-treated rats, AT2R-induced contraction was absent in parallel with the strong decrease in ROS level. Thus, hydralazine most probably suppressed AT2R-induced contraction thanks to its antioxidant property. This observation is in agreement with previous studies demonstrating that hydralazine is an antioxidant.34 Second, FMD might also be improved because of the increased bioavailability of NO found in arteries from hydralazine-treated old rats. Indeed, this effect might also be associated with the antioxidant property of hydralazine. We found that the level of ROS in mesenteric arteries was decreased after treatment with hydralazine in both endothelial and smooth muscle cells. This is in agreement with previous studies showing that a reduction in ROS production in response to flow, in diabetic animals, restores FMD to the control level.35
Perspectives
We identified an important change in AT2R function in aging, because AT2R stimulated by flow (endogenous angiotensin II) or by exogenous angiotensin II induced a contraction involving the production of ROS. This contraction contributed to lower FMD. This alteration might affect the efficiency of the treatments used to fight vascular disorders in old patients. This observation is especially important, because the occurrence and severity of vascular diseases is largely related to vascular aging.36 In addition, hydralazine improved FMD in resistance arteries from old rats, showing that the alteration is reversible. Hydralazine decreased ROS level in both endothelial and smooth muscle cells, thus improving FMD. This effect was because of the suppression of AT2R-induced contraction and through an increase of the NO availability.
Interestingly, the positive effect of hydralazine on FMD in old rats is comparable to the effect of exercise training.37 Both hydralazine and exercise increase blood flow and FMD. Thus, the present finding also provides a possible explanation for the beneficial effect of exercise training on resistance arteries in the elderly. Nevertheless, exercise training is not always possible or safe in the older patients. In this situation, hydralazine or other vasodilator treatment (to be tested) might be an alternative when improving endothelium-dependent tone is necessary.
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Acknowledgments |
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Sources of Funding
This work was supported in part by a grant from the French Foundation for Medical Research (Paris, France). F.P. was supported by a grant from the French Federation of Cardiology (Paris, France). A.B. was supported by the Conseil Général du Maine et Loire. O.D. was supported by the Pays de la Loire Region. C.B. and D.H. were supported by an interface grant (Contrat d’Interface INSERM-CHU d’Angers).
Disclosures
None.
Received November 22, 2006; first decision December 14, 2006; accepted April 12, 2007.
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