Published online before print December 5, 2005, doi: 10.1161/01.HYP.0000196272.79321.11
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(Hypertension. 2006;47:122.)
© 2006 American Heart Association, Inc.
Original Articles |
Role of Angiotensin Type-1 and Angiotensin Type-2 Receptors in the Expression of Vascular Integrins in Angiotensin II–Infused Rats
From the Experimental Hypertension Laboratory (P.B., F.A., E.L.S.) and Laboratory of Cellular Biology of Hypertension (G.T.), Canadian Institutes of Health Research Multidisciplinary Research Group on Hypertension, Clinical Research Institute of Montreal, Montreal, Quebec, Canada.
Correspondence to Ernesto L. Schiffrin, Clinical Research Institute of Montreal, 110 Pine Ave West, Montreal, Quebec, Canada H2W 1R7. E-mail ernesto.schiffrin{at}ircm.qc.ca
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Abstract |
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Angiotensin II plays an important role in vascular remodeling through effects that involve, in part, interactions of vascular smooth muscle cells with extracellular matrix via integrins, which belong to a family of transmembrane receptors. We hypothesized that angiotensin (Ang) II regulates expression of vascular integrins and their ligands in experimental hypertension. Rats were infused subcutaneously with Ang II and received angiotensin type-1 (AT1) receptor blocker losartan, the AT1/angiotensin type-2 (AT2) [Sar1-Ile8]-Ang II, or the vasodilator hydralazine for 7 days. Osteopontin and integrin subunit expression were evaluated immunohistochemically. Ang II enhanced vascular
8, ß1, ß3 integrins and osteopontin expression, which were significantly reduced by losartan, [Sar1-Ile8]-Ang II, and hydralazine. Although Ang II increased vascular 5 subunit expression, this was additionally increased by losartan. Losartan was the only treatment that induced 1 subunit expression. These results demonstrate that AT1 and AT2 receptors have countervailing effects on vascular integrin subunit expression that may influence their effects on vascular remodeling and extracellular matrix composition.
Key Words: renin-angiotensin system • aorta • extracellular matrix • hypertension • osteopontin
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Introduction |
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Migration of vascular smooth muscle cells (VSMCs) within or from the media to the intima plays a major role in arterial remodeling in atherosclerosis and hypertension. Migration of VSMCs and remodeling require controlled degradation of extracellular matrix (ECM) proteins by matrix metalloproteinases (MMPs) and the activation or release of growth factors. VSMCs are embedded in ECM that includes collagens, fibronectin, laminin, elastin, and proteoglycans.1 The composition of the ECM can change in response to vascular injury. For example, the ECM protein tenascin, absent in normal rat aortic media, is expressed in the neointima in hypertension or after injury.2,3
Several receptor–ligand systems, such as integrins, are involved in cell–ECM interactions, which regulate cell phenotype and function. Integrins belong to a superfamily of transmembrane glycoprotein adhesion receptors consisting of 2 noncovalently linked subunits, and ß. To date, at least 18 subunits and 8 ß subunits have been described, with a resulting combination of >22 integrins with varying ligand specificity.4 The surrounding ECM, as well as integrin–matrix interactions, regulate a variety of cell behaviors, including migration,5,6 proliferation,7 proteinase production, and differentiation.8–10
During the processes of VSMC migration from the media to the intima, cells dissociate from and degrade the ECM proteins. This process involves 3 steps: a phenotypic change from the contractile to the synthetic state, proteolysis of ECM proteins, and cell migration through matrix digestion, a process that resembles tumor cell invasion.11
Remodeling of the small arteries occurs in both human and experimental models of hypertension and involves changes in ECM and its interactions with VSMCs. Restructuring of VSMCs may be, in part, triggered by adhesion molecules, such as integrins, which transduce signals from the extracellular environment to cytoskeletal fibrillar components.12,13 Changes in ECM components and the corresponding adhesion receptors and interactions between VSMC and matrix proteins may result in rearrangement of these components of the vascular wall. Thus, fibronectin, laminin, and integrins participate in resistance artery remodeling.14 MMP activation is also necessary for VSMC migration. Recent evidence supports the concept that MMPs play an important role in VSMC migration into the intima in the balloon-injured carotid artery.15–17
We demonstrated previously that small artery remodeling in angiotensin (Ang) II–induced hypertension was mediated by both angiotensin type-1 (AT1) and angiotensin type-2 (AT2) receptors through alteration of activity of MMPs and of tissue inhibitors of metalloproteinases (TIMPs), which affected ECM content and vascular mechanics of resistance vessels.18 We now hypothesized that, as a result of changes in ECM components and their corresponding adhesion receptors, cell–matrix interactions would lead to a rearrangement of VSMCs and restructuring of the vascular wall. Accordingly, we questioned whether changes in the expression of the various vascular integrins in Ang II–infused rats result from regulation by AT1 and/or by AT2 receptors, using a selective AT1 or a combined AT1/AT2 receptor antagonist.
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Methods |
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Antibodies and Reagents
All of the reagents were from Sigma Chemicals unless otherwise noted. Sar-Ile was purchased from Bachem, whereas anti-
1 subunit and anti-ß3 subunit antibodies were from Chemicon. Osteopontin antibody was purchased from Santa Cruz Biotechnologies. Anti-5 and anti-ß1a antibodies were generous gifts from Dr. R. Hynes (Howard Hughes Medical Institute, Chevy Chase, MD) and Dr. P. Liu (Toronto General Hospital, Toronto, Ontario, Canada), respectively. Antiserum to the 8 subunit was generated as described elsewhere,19 and all of the secondary antibodies were from Vector Laboratories.
Animal Experiments
The study protocol was approved by the Animal Care Committee of the Clinical Research Institute of Montreal and performed following recommendations of the Canadian Council of Animal Care. Male Sprague Dawley rats (Charles Rivers), housed under controlled conditions, were infused with Ile5-Ang II (120 ng/kg per minute; Calbiochem) via osmotic minipumps (Alzet Corp).18 The selective AT1 receptor antagonist losartan (10 mg/kg per day) and the vasodilator hydralazine (25 mg/kg per day) were given in the drinking water, whereas the combined AT1/AT2 receptor antagonist Sar-Ile was infused via osmotic minipumps (10 µg/kg per minute), all for 7 days. Systolic blood pressure (SBP) was measured by the tail-cuff method as described previously,18 and rats were then killed humanely.
Integrin and Osteopontin Immunohistochemistry
Aortas were fixed in Russel fixative and embedded in paraffin. Endogenous peroxidase in 5-µm–thick sections was quenched by incubation with 0.3% H2O2 in 0.03% Tween 20-Tris buffer (TBT) for 30 minutes. Nonspecific binding was blocked by incubation in 10% normal serum in TBT. All of the antigens were detected by overnight incubation with the appropriate antibody in TBT containing 10% normal serum in a humidified chamber. Primary antibodies were revealed by secondary antibodies coupled to a biotin—avidin–peroxidase complex (Vectastain ABC kit, Vector Laboratories). Peroxidase activity was detected with 1 mg/mL diaminobenzidine tetrahydrochloride and 0.2% H2O2. Sections were counterstained with hematoxylin (Vector Laboratories), visualized with Zeiss Axiophot 100M microscope (Carl Zeiss Microimaging Inc), and analyzed with Northern Eclipse image analysis software (Empix Imaging Inc). Staining was corrected by the surface area. Nonspecific staining was verified by the replacement of primary antibody by appropriate normal serum.
Statistical Analysis
Data are presented as mean±SEM. Immunohistochemistry quantification was analyzed by 1-way ANOVA followed by a Student–Newman–Keuls test. P<0.05 was considered statistically significant.
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Results |
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Vascular Integrin Subunit Expression
Vascular integrin
1 subunit expression was unaffected by Ang II or concomitant treatment with either Sar-Ile or hydralazine but was significantly increased after AT1 receptor blockade with losartan (P<0.001 versus all groups; Figure 1 and Figure I, available online at http://www.hypertensionaha. org). Vascular expression of integrin 5 subunit was significantly increased by Ang II (P<0.05 versus control; Figure 2 and Figure II, available online) and further increased by losartan (P<0.001 versus control, P<0.01 versus Ang II; Figure 2), whereas it decreased significantly with Sar-Ile (P<0.001 versus Ang II and losartan, P<0.01 versus control; Figure 2) and hydralazine (P<0.001 versus Ang II and losartan, P<0.05 versus control; Figure 2). Ang II induced integrin 8 subunit expression (P<0.001 versus control, Figure 3 and Figure III, available online), which was reduced by losartan (P<0.001 versus Ang II; Figure 3). 8 subunit expression was not decreased by either Sar-Ile (P<0.001 versus Ang II, P<0.01 versus control) or hydralazine (P<0.001 versus Ang II; Figure 3). Ang II–induced expression of ß1 and ß3 subunits (Figures 4 and 5
and Figures IV and V, available online) was significantly lowered by losartan, Sar-Ile, and hydralazine (Figures 4 and 5).
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P<0.001 vs Ang II; 
P<0.001 vs Ang II + Los; 
P<0.01 vs Control; ||P<0.01 vs Ang II; ¶P<0.05 vs Control.
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Osteopontin Expression
Osteopontin expression was significantly increased by Ang II (P<0.001 versus control; Figure 6 and Figure IV, available online), and this was partially blocked by losartan (P<0.001 versus Ang II, P<0.05 versus control) and abrogated by Sar-Ile and hydralazine (P<0.001 versus Ang II, P<0.05 versus losartan).
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Discussion |
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We reported previously that dual blockade of AT1/AT2 receptors with Sar-Ile compared with AT1 receptor blockade with losartan differentially altered the structure, mechanics, and composition of small mesenteric resistance arteries in response to Ang II infusion, in association with changes in MMP-2 activity and TIMP-2 binding.18 These findings led us to investigate here the possible role of vascular integrins and their ligands in the changes observed in Ang II–infused rats treated with AT1 or combined AT1/AT2 receptor antagonists. In this previous study, we found that SBP was significantly increased by 7-day Ang II infusion (177±7 versus 113±2 mm Hg, controls; P<0.001) and that this increase was significantly blunted by losartan (139±4 mm Hg), hydralazine (134±7 mm Hg), and Sar-Ile (154±7 mm Hg). Despite no significant differences in the effectiveness of BP reduction between dual AT1/AT2 antagonism by Sar-Ile and that of specific AT1 antagonism by losartan, Sar-Ile–treated animals showed a trend to higher SBP values.18 The present study demonstrates a differential role for AT1 and AT2 receptors in the regulation of vascular integrin expression. Expression of integrin
and ß subunits was altered after a blockade of AT1 receptors alone or both AT1 and AT2 receptors. In addition to differential integrin subunit expression, osteopontin, which has high affinity for several integrins, also increased after Ang II infusion and was differentially regulated by AT1 and AT2 receptors.
Increased VSMC proliferation and migration contribute to the pathogenesis of hypertension.20 A large number of agents and mechanisms (growth factors, ECM, cell–cell interactions, etc.) regulate VSMC growth and migration,20,21 but precise cellular signaling mechanisms involved have not been completely elucidated. Kohno et al22 showed in vitro that Ang II via the AT1 receptor stimulates migration and proliferation of human coronary artery smooth muscle cells. Ang II, via AT1 receptors, increased cardiac fibroblast adhesion through the activation of multiple signaling pathways, which include upregulation of osteopontin and v, ß3, and ß5 integrins, leading to the development of left ventricular hypertrophy in spontaneously hypertensive rats.23
In the present study, expression of 1 integrin subunits, one of the major integrin receptors for collagen, was increased after AT1 antagonism. This was prevented by a blockade of AT1 and AT2 receptors with Sar-Ile, which suggests that AT2 receptors are implicated in the expression of this integrin subunit. Because of opposing effects of AT1 and AT2 receptors on blood pressure (BP), AT1 receptor stimulation could inhibit 1 subunit expression. Thus, the simultaneous blockade of AT1 and AT2 receptors would result in reduced effects relative to the selective blockade of AT1 receptors. 1 integrin mediates collagen-triggered signaling and has been proposed to signal through the Ras/Shc/mitogen-activated protein kinase pathway, which inhibits MMP synthesis.24 In 1 integrin subunit null mice, angiogenesis was reduced.25 It has accordingly been suggested that this results from excess MMP activation with the inhibition of angiogenesis via the generation of angiostatin from circulating plasminogen, which demonstrates the potential of Ang II- regulated 1 subunit–containing integrins to influence remodeling of the vasculature.
The 5 integrin subunit, which is part of 5ß1 integrin, the fibronectin receptor, and involved in fibronectin polymerization,26 was significantly increased by Ang II and additionally enhanced by AT1 antagonism but reduced by concomitant AT1 and AT2 blockade. This result suggests a role for AT2 receptors in the regulation of 5 integrin subunits. The interaction between the fibronectin receptor 5ß1 integrin27 and the arginine-glycine-aspartic acid (RGD) site of fibronectin28 is required for matrix assembly in most cellular systems.29,30 This is important for VSMC proliferation, because inhibition of fibronectin matrix assembly inhibits VSMC proliferation,31 which may explain, in part, our previous result showing abrogation of growth in resistance arteries after Sar-Ile administration. This occurred despite significant increase in fibronectin, which we demonstrated is modulated by AT2 receptors.18 In support of our findings, Chassagne et al32 demonstrated that AT2 receptor activation inhibited VSMC migration through fibronectin secretion and subsequent VSMC attachment. It is therefore possible that 5 subunit expression, which can mediate cell attachment to fibronectin, is associated with a nonmigratory VSMC phenotype.
Ang II significantly increased vascular 8 subunit expression, similar to what was shown previously with cardiac fibroblasts.33 This increase may be BP dependent, because it was prevented by losartan, Sar-Ile, and hydralazine. 8 integrin expression is associated with induction of the contractile phenotype, because its upregulation was reported to occur in association with a differentiation of fibroblasts into myofibroblasts19 and a reduction in migratory phenotype.34
The regulation of the 2 major ß subunits participates in the overall expression and function of integrins. The expression of the ß1 subunit was significantly increased after Ang II infusion. This increase was prevented by all of the treatments, suggesting that the regulation of ß1 subunits is BP dependent, similar to that of 8 subunits, which are associated with them.35 Expression of the ß3 subunit, also increased by Ang II, was abrogated by losartan, in opposition to the ß1 subunit, the expression of which was only partially blunted by AT1 antagonism. ß3 subunit expression was unaltered by dual AT1/AT2 antagonism and hydralazine. Thus, ß3 subunit expression may be under AT1 receptor regulation, as reported previously by Kawano et al.23 ß3 and v subunits, which form the vß3 integrin, play a critical role in cell proliferation and migration and, accordingly, in vascular remodeling.36
Another RGD-containing protein that may be associated with VSMC proliferation is osteopontin, a soluble secreted phosphoglycoprotein, which plays a role in VSMC adhesion with vß3 integrin.37,38 Although numerous functions have been attributed to osteopontin in vitro, the in vivo function remains less defined. Osteopontin may be regulated by Ang II and can modulate Ang II–induced fibrosis.39,40 Osteopontin may serve as a negative modulator of integrin–ECM interactions.41 Extending our previous work, we show that osteopontin expression is partially affected by AT1 antagonism and additionally decreased by combined AT1 and AT2 receptor blockade and by hydralazine, which suggests that it is regulated by BP similar to the 8 and ß1 integrin subunits. It is noteworthy that most vascular integrin subunits, as well as osteopontin expression, were partially reduced by hydralazine, suggesting a pressure-dependent effect. However, the observed effect may not be merely BP dependent.18,42 It has been suggested that vascular integrins are not only mechanosensors for shear and tension but can also participate in the control of vascular tone.43 The selective AT1 receptor blockade lowered SBP and improved vascular remodeling in Ang II–infused rats, which did not occur with hydralazine despite similar SBP lowering.18 In addition, because 8, ß1, and ß3 subunit expression levels were similar in these groups, this allows the conclusion to be drawn that these subunits do not play a role in vascular remodeling in this model.
VSMC behavior in the media of blood vessels and their role in vascular remodeling may be modulated by several ECM proteins, such as fibronectin and ligands for 5ß1, 8ß1, and vß3. These integrins have been shown to play a role in cellular events including differentiation, development, wound healing, adhesion, and cell migration. Hedin et al44 demonstrated that fibronectin and MMP synthesis are involved in the conversion of the VSMC phenotype from contractile to synthetic. Therefore, it is plausible that, in the absence of Ang II receptor activation, VSMC phenotype is migratory rather than contractile, as shown when AT1 receptors are blocked.45 When both AT1 and AT2 receptors were blocked, there was less TIMP-2 binding to MMP-2 and more MMP-2 activity, and, consequently, more ECM degradation and growth was abrogated. These results are supported by the present data, because there was a decrease of most integrin subunits, such as 8ß1 integrin, responsible for a reduction in VSMC anchoring to the surrounding ECM, and, consequently, possible emergence of a synthetic, migratory, and nonproliferative phenotype.
There are limitations to this study. The use of a selective AT2 receptor antagonist alone or in combination with losartan would have been informative, but because of limited availability and prohibitive high cost, this could not be performed and was replaced by Sar-Ile. By using Sar-Ile, a combined AT1/AT2 antagonist, we obtained evidence of a role for AT2 receptors by comparison with the effect of a selective AT1 receptor antagonist. We have discussed a change to a migratory phenotype represented by a differential regulation of integrins associated with this phenotype, but in this in vivo study we have not actually demonstrated the presence of this phenotype. The association of certain integrins with a VSMC migratory phenotype has been shown previously by others.34,46
In conclusion, the blockade of AT1 or both AT1 and AT2 receptors in Ang II–infused rats differentially modulated integrin and osteopontin expression, which may result in a different VSMC phenotype. Whereas AT1 receptors enhance vascular 8, ß1, and ß3 integrin subunit expression and osteopontin deposition and reduce 1 integrin expression, AT2 receptors increase the expression of 1 and 5 integrin subunits.
Perspectives
These results demonstrate the differential importance of AT1 and AT2 receptors in the regulation of vascular integrins in Ang II-induced hypertension. Regulation of integrins and their implication in vascular remodeling or in cell phenotypic changes by AT1 and AT2 receptors may explain in part different effects of Ang-converting enzyme inhibitors and Ang receptor blockers on cardiovascular risk reduction in various cardiovascular conditions.
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Acknowledgments |
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This work was supported by grant 13570 (to E.L.S.) and a Group Grant to the Multidisciplinary Research Group on Hypertension, both from the Canadian Institutes of Health Research. We are grateful to Suzanne Diébold and André Turgeon for their excellent technical assistance and to Annie Vallée and Dr Fatiha Bouzeghrane for assistance in histology and scientific advice, respectively.
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Footnotes |
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This paper was sent to Sigmund D. Curt, associate editor, for review by expert referees, editorial decision, and final disposition.
Received August 24, 2005; first decision September 8, 2005; accepted October 25, 2005.
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