Published online before print March 8, 2004, doi: 10.1161/01.HYP.0000123074.89717.3d
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(Hypertension. 2004;43:1074.)
© 2004 American Heart Association, Inc.
Scientific Contributions |
Angiotensin II–Induced Vascular Dysfunction Is Mediated by the AT1A Receptor in Mice
From the Departments of Internal Medicine (M.J.R., S.P.D., S.M. F.M.F., C.D.S.), Pharmacology (F.M.F.), and Physiology and Biophysics (C.D.S.), Cardiovascular Center, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City.
Correspondence to Michael J. Ryan, PhD, Department of Internal Medicine, University of Iowa, 3181 MEBRF, Iowa City, IA 52242. E-mail ryanm{at}physiology.uiowa.edu
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Abstract |
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Many of the actions of angiotensin II (Ang II) are mediated by angiotensin type 1 receptors (AT1), of which there are 2 pharmacologically indistinguishable subtypes (AT1A and AT1B). The purpose of this study was to evaluate the effect of an AT1A homozygous deletion (AT1A–/–) on vascular reactivity. AT1A–/– mice and control littermates (AT1A+/+) were infused with vehicle (saline) or Ang II (1000 ng · kg–1 · min–1) for 7 days by osmotic pumps. Systolic pressure was increased in AT1A+/+ mice (
45±8 mm Hg, P<0.0001) but unchanged in AT1A–/– mice (5±3 mm Hg, P>0.13) on day 7. The carotid artery response to the vasodilators acetylcholine (ACh), nitroprusside, and papaverine and to the vasoconstrictors phenylephrine, U46619, 5-hydroxytryptamine (5-HT), and KCl were not different between vehicle-infused AT1A+/+ and AT1A–/– animals. Carotid relaxation to ACh was impaired and contraction to 5-HT was increased in Ang II–infused AT1A+/+ mice. Ang II did not affect carotid responses in AT1A–/– mice. Superoxide, measured by lucigenin (5 µmol/L), and hydroethidine staining were not different between AT1A+/+ and AT1A–/– mice after vehicle or Ang II infusion, suggesting that it was not contributing to the altered ACh and 5-HT responses. The Rho-kinase inhibitor Y-27632 (1 µmol/L) attenuated the 5-HT response in both vehicle- and Ang II–infused AT1A+/+ mice. Moreover, concentration-dependent relaxation to Y-27632 and RhoA protein expression were not different in vehicle- or Ang II–infused AT1A+/+. These data demonstrate that the AT1A receptor is required for Ang II–induced changes in carotid artery function.
Key Words: endothelium • receptors, angiotensin II • carotid arteries • acetylcholine
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Introduction |
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Angiotensin II (Ang II) is critical for the regulation of vascular tone, blood pressure, and volume homeostasis. High levels of circulating Ang II can cause impaired vascular function, mediated in part by stimulating NADPH oxidase activity to increase superoxide levels.1–4 The physiological actions of Ang II occur through its binding to 2 main cell surface receptors, AT1 and AT2. The effects of Ang II in the vasculature are widely considered to result from AT1 activation. In rodents, however, 2 AT1 receptor subtypes (AT1A and AT1B) share 94% sequence homology5 and are pharmacologically indistinguishable. Therefore, investigators have used mice with gene-targeted mutations in the AT1A6 or AT1B7 receptor to better understand the physiological role for each.
Mice with a homozygous deletion of the AT1A subtype (AT1A–/–) have reduced blood pressures and no pressor response to Ang II infusion.6 These data implicate AT1A as the primary subtype responsible for Ang II actions in mice. However, some reports suggest a potential role for AT1B in the vasculature.8–11 For example, recent evidence implicates AT1B as the predominant mediator of Ang II–induced contraction in the abdominal aorta and femoral arteries.12 Although several investigators have addressed the differential role of AT1A and AT1B in Ang II–induced contraction,8,11,13 there are no reports aimed at investigating the contribution of Ang II receptor subtypes to nitric oxide–mediated vessel relaxation, non-Ang II contractile responses, or the generation of vascular superoxide. Therefore, we tested whether a genetic deletion of the AT1A receptor: (1) alters vascular responses to dilators and constrictors; (2) protects the vessels from Ang II–induced changes in reactivity; and (3) changes basal and Ang II–stimulated levels of vascular superoxide.
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Methods |
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Animals
Mice heterozygous for the AT1A receptor subtype (+/–) were obtained from the Jackson Laboratory (Bar Harbor, Me). The colony was maintained on a mixed genetic background (
87% 129P3/J and 13% C57BL/6J), and littermates were used as controls. Offspring were born in ratios (+/+ 25%, +/– 62%, –/– 13%) similar to those reported by Oliverio et al.14 Experiments were performed on male and female mice at an average age of 6.0±0.3 (AT1A+/+) and 5.8±0.4 (AT1A–/–) months.
Reagents
Acetylcholine (ACh), sodium nitroprusside (SNP), papaverine (PAP), phenylephrine (PE), Ang II, and 5-hydroxytryptamine (5-HT) were purchased from Sigma Chemicals and dissolved in saline. Lucigenin (Sigma) was dissolved in phosphate-buffered saline. Hydroethidine (Molecular Probes) was prepared as described previously.1,15 U46619 (Cayman Chemicals) was dissolved in 100% ethanol with a subsequent dilution in saline. Y-27632 (Calbiochem) was dissolved in saline.
Protocol
Mice were infused for 7 days with vehicle (saline) or a pressor dose of Ang II (1000 ng · kg–1 · min–1) with an osmotic minipump (Alzet) implanted subcutaneously.16 Subsequently, the carotid artery was isolated to evaluate vessel reactivity and superoxide (hydroethidine). The thoracic aorta was used to assess protein expression, RNA expression, and superoxide (lucigenin). The University of Iowa Animal Care and Use Committee approved all experimental protocols.
Blood Pressure
Systolic pressure (mm Hg) was monitored in mice with the use of an automated tail-cuff machine (Visitech Systems).1,15,17
Vascular Reactivity
Carotid artery tension was measured in ex vivo organ chamber baths. Rings were precontracted with U46619 before testing for vessel relaxation.1,15,17,18
Superoxide
Aortic and carotid segments were used to assess vascular superoxide with the lucigenin (5 µmol/L) chemiluminescent assay and hydroethidine assay, respectively.1,15
Western Blot
Western blotting from aortic protein extracts was performed as previously described.19 The RhoA antibody was purchased from Santa Cruz.
Real-Time Reverse-Transcription Polymerase Chain Reaction
Total aortic RNA was prepared with the TriReagent (MRC). The reverse transcription (RT) reaction was performed with an Invitrogen Superscript III, and real-time quantitative polymerase chain reaction (PCR) was performed with a Bio-Rad Icycler. Expression of AT1A, AT1B, and AT2 receptors was assessed in AT1A+/+ and AT1A–/– mice treated with either vehicle or Ang II. SYBR green was used, and data were corrected for the expression of 18s rRNA. Primer sequences are available on request.
Statistics
A 1-way ANOVA with repeated measures or a 1-way ANOVA was used to compare blood pressure and vascular function data or superoxide data. A Student-Newman-Keuls post hoc test was applied. Values were considered different when P<0.05 and was also different between strains. For example, for AT1A+/+ Ang II to be considered different from AT1A+/+ vehicle, it also needed to be statistically different from AT1A–/– mice.
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Results |
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This study was designed to examine putative vascular changes caused by a gene-targeted deletion of the AT1A receptor (AT1A–/–). Baseline systolic pressure was lower in AT1A–/– compared with controls (AT1A+/+), consistent with previous reports.6 A 7-day infusion of Ang II caused a significant increase in pressure by day 2 that remained elevated during the remaining days in AT1A+/+ mice. There was no effect of Ang II infusion on blood pressure in AT1A–/– mice (Figure 1).
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different from days 1 to 3 of AT1A+/+.Because Ang II is important in the maintenance of vascular tone, we tested whether carotid responses to vasodilators were different in AT1A–/– mice relative to AT1A+/+ mice. In vehicle-infused mice, carotid artery rings from AT1A+/+ and AT1A–/– responded similarly to ACh (Figure 2A), SNP (Figure 2B), and PAP (Figure 2C). After Ang II infusion, responses to SNP and PAP were not different in AT1A+/+ and AT1A–/–. In addition, Ang II infusion did not change the ACh response in AT1A–/– mice. However, the response to ACh was significantly impaired in carotid arteries from Ang II–infused AT1A+/+ mice (Figure 2A).
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We also tested whether the absence of AT1A would alter carotid responses to vasoconstrictors. There was no difference in contractile responses to PE (Figure 3A), U46619 (Figure 3B), KCl (Figure 3C), or 5-HT (Figure 4A) between AT1A+/+ and AT1A–/– under vehicle-infused conditions. However, responses to 5-HT were markedly enhanced in the AT1A+/+ mice (but not the AT1A–/– mice) after Ang II infusion (Figure 4A). Because 5-HT can cause contraction through RhoA/Rho-kinase signaling,20,21 we repeated the 5-HT concentration-response experiment after a 30-minute incubation with the Rho-kinase inhibitor Y-27632 (1 µmol/L) and found that it attenuated the response to 5-HT in Ang II–infused mice (and Ang II–infused AT1A–/– mice; Figure 4A). Y-27632 also significantly reduced 5-HT contraction in the vehicle-infused AT1A+/+ and AT1A–/– mice, confirming the importance of Rho-kinase in 5-HT–induced contraction. Y-27632 also attenuated carotid U46619-induced (n=4) and PE-induced (n=2) contractions in vehicle-infused AT1A+/+ mice to a similar extent as Ang II–infused AT1A+/+ mice (data not shown). Both U46619 and PE have been shown to cause RhoA/Rho-kinase–mediated contraction.22 To further examine whether the enhanced 5-HT contraction was due to increased RhoA/Rho-kinase signaling, concentration-dependent relaxations to Y-27632 were examined in carotid arteries from vehicle- and Ang II–infused AT1A+/+ mice (Figure 4B). In addition, RhoA protein expression was evaluated by Western blot in total membrane and soluble fractions from AT1A+/+ and AT1A–/– mice. Figure 4C shows a representative blot from 3 experiments, along with summary data presented as a ratio of total membrane to soluble RhoA. The concentration response to Y-2763221 and the ratio of RhoA in the membrane and cytosol23 have been used by other investigators as an indicator of Rho signaling activity. However, there were no differences detected between vehicle- and Ang II–infused mice.
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AngII is known to increase the production of vascular superoxide through activation of NADPH oxidases.1,24–29 Therefore, we examined aortic or carotid superoxide levels as a potential mechanism for the altered carotid responses mentioned earlier. Baseline superoxide was not different between AT1A+/+ and AT1A–/– after vehicle infusion by the lucigenin chemiluminescent assay or hydroethidine staining (Figure 5A and 5B). We hypothesized that after a 7-day infusion of Ang II, AT1A+/+ mice would have higher vascular levels of superoxide, whereas AT1A–/– mice would not exhibit such a change. Surprisingly, superoxide was not detectably different in either group after Ang II infusion, suggesting that elevated superoxide might not be contributing to the altered vascular reactivity in the Ang II–infused AT1A+/+ mice (Figure 5A and 5B).
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Finally, real-time RT-PCR was used to evaluate aortic expression of AT1A, AT1B, and AT2 receptors after vehicle or Ang II infusion. The data are presented as the fold change relative to vehicle-treated AT1A+/+ mice, the value for which was set equal to 1. The AT1A primer set amplified single products in both AT1A+/+ and AT1A–/– mice. However, the product from AT1A–/– mice was in much lower abundance and had a different melting profile, indicating that, as expected, the AT1A receptor was not expressed in the AT1A–/– mice. Ang II did not alter AT1A expression in AT1A+/+ mice (Figure 6A). On average, AT1B expression was lower by almost half (amplifying 0.8±0.2 cycles later than AT1A) compared with AT1A. AT1B expression was not statistically different among the groups (Figure 6B). The AT2 receptor was detectable in only 1 of 3 samples from each vehicle-treated group (amplifying 8.2±0.7 cycles later than AT1A). After Ang II infusion, AT2 expression increased and was detectable in 2 of 3 samples in both AT1A+/+ and AT1A–/– groups (Figure 6C).
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Discussion |
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This study was aimed at addressing whether a genetic deletion of the AT1A receptor subtype alters nitric oxide–mediated relaxation, vessel contraction, and superoxide levels after infusion of vehicle or Ang II. There are 2 main findings. First, the data suggest an important role for AT1A in mediating Ang II–induced changes in vascular function, given that Ang II infusion did not cause changes in the carotid responses of AT1A–/– mice. Second, the data show that a gene-targeted deletion of the AT1A receptor does not affect baseline vascular function or superoxide.
The AT1A–/– mouse model was originally developed by Coffman and colleagues. The mice have lower blood pressure than do control littermates, and pressor responses to Ang II infusion are absent.6 Our blood pressure data are consistent with these observations. The AT1A–/– model has been used previously to examine putative differences in the function of AT1A and AT1B. Although much of the data support AT1A as being responsible for most of the physiological effects of Ang II, there are data implicating AT1B in blood pressure, vascular tone, and volume regulation. First, divergent roles for AT1 receptors have been identified in the murine brain, with the pressor and dipsogenic responses mediated by AT1A and AT1B receptors, respectively.30 Second, infusion of Ang II can elicit a pressor response in AT1A–/– mice pretreated with an angiotensin-converting enzyme inhibitor.10 Third, vascular smooth muscle from AT1A–/– has normal calcium signaling in response to Ang II.9 Fourth, in the absence of AT1A receptors, Ang II can cause constriction in the renal microvasculature.8,11,13 Finally, contraction of the abdominal aorta and femoral arteries to Ang II appears to be mediated by AT1B receptors.12 The latter lines of evidence in particular indicate that both AT1A and AT1B play important roles in mediating the vascular responses to Ang II. However, our data suggest that AT1A is necessary to mediate Ang II–induced changes in vascular reactivity. It is important to recognize that AT1A–/– mice have high circulating levels of Ang II that might mask the physiological importance of AT1B.10 Therefore, to truly investigate the role of AT1B, a series of experiments with AT1A–/– mice treated with an angiotensin-converting enzyme inhibitor as well as AT1B-knockout mice needs to be designed.
In the present study, we examined expression of the various Ang II receptor subtypes. Our finding that AT1B expression is approximately half that of AT1A in AT1A+/+ mice is consistent with what has been reported in cultured aortic smooth muscle from wild-type mice.9 Given that AT2 is not abundantly expressed in the adult animal, we were not surprised that detectable expression was at the limits of our assay. Although the data are not definitive, it is interesting to note that AT2 expression was more readily detectable in Ang II–infused mice and that the expression level was higher. Other investigators have reported an increase in AT2 receptor expression after Ang II infusion.31 An increase in AT2 receptors during Ang II infusion might reflect a compensatory effect, given that AT2 activation is thought to have vascular protective effects.
Because circulating Ang II is high in AT1A–/– mice, the similarity in basal superoxide levels with AT1A+/+ mice might reflect a tonic stimulation of AT1B receptors. It is possible that AT1B-mediated superoxide production might compensate for the loss of AT1A and therefore, maintain a similar basal superoxide level. However, on the basis of the vessel function data, we predicted that Ang II infusion would not alter superoxide levels in AT1A–/– mice but would cause an increase in superoxide in the AT1A+/+ mice. Our laboratory and several others have demonstrated that high levels of circulating Ang II can cause an increase in vascular superoxide.1,24–29 Therefore, it was surprising to find that after Ang II infusion, there were no changes in vascular superoxide levels in AT1A+/+ mice. The reason for this anomalous result is not clear, although it is possible that the genetic background of the mice might be a contributing factor. The mice in the present study are of a mixed genetic background (129P3/J and C57BL/6J), whereas mice in the aforementioned studies were C57BL/6J.1,24–29 Indeed, we have reported that there are blood pressure and vascular reactivity differences among various inbred strains, with 129P3/J having particularly divergent phenotypes.17 Nevertheless, in the absence of a definitive explanation, these data do not support a major role for superoxide in the Ang II–induced changes in vascular reactivity from the AT1A+/+ mice from the present study.
Because superoxide levels were not different, consideration was given to other possible mechanisms for the change in vascular reactivity in Ang II–infused AT1A+/+ mice. In particular, we focused on the marked increase in the carotid response to 5-HT caused by Ang II infusion. Importantly, there is evidence to suggest that 5-HT responses might be a sensitive indicator of altered endothelial function.32 The net effect of 5-HT in the vasculature is the result of a balance between its actions on endothelial cells to cause relaxation and its interaction with smooth muscle to cause contraction.33 The increase in 5-HT contraction after Ang II infusion is consistent with a shift in that balance, suggesting an impairment of endothelial function. This is further supported by the fact that the carotid response to the endothelium-dependent dilator ACh was impaired but the response to SNP, PAP, or any of the other contractile agonists was not altered. The Ang II–induced changes in 5-HT contraction but not other agonists also demonstrate that Ang II infusion was not causing a global increase in vessel contractility.
Vasoconstriction to 5-HT is due in large part to RhoA/Rho-kinase–mediated smooth muscle in vascular and cardiac muscle.34–37 We hypothesized that the enhanced 5-HT response in Ang II–infused AT1A+/+ mice was due to increased RhoA/Rho-kinase signaling. To examine this possibility more fully, experiments were repeated with the selective Rho-kinase inhibitor Y-27632. Although the presence of the inhibitor seemed to normalize the 5-HT response in Ang II–infused AT1A+/+ mice, it also markedly decreased the 5-HT response in vehicle-infused mice. Contractile responses to U46619 and PE, which are dependent on RhoA/Rho-kinase signaling,17,22 were also attenuated in the presence of Y-27632. Because the 5-HT response was attenuated to a similar degree by Y-27632, it is difficult to interpret these data to mean that RhoA/Rho-kinase signaling was enhanced after Ang II infusion in AT1A+/+ mice. Therefore, to further investigate the potential role of Rho-kinase signaling in the enhanced 5-HT response, concentration-response curves to Y-27632 were performed. If Rho-kinase signaling were increased by Ang II infusion, the concentration-dependent relaxation to Y-27632 should be enhanced.21 However, this was not the case. Finally, it is known that on activation, RhoA is recruited to the membrane.23 Therefore, the amount of RhoA in total membrane and soluble protein fractions can be used as an index of RhoA/Rho-kinase activity. Our Western blot data indicate that the distribution of RhoA in the aorta was not changed by Ang II infusion in either AT1A+/+ or AT1A–/– mice. These data argue strongly against a change in Rho-kinase signaling being the mechanism for enhanced 5-HT induced contraction.
Perspectives
Although there is 1 report to the contrary,38 it is widely believed that humans do not possess multiple AT1 receptor subtypes. Despite this, rodents (which have both AT1A and AT1B subtypes) have been widely used to study the effect of Ang II to cause impaired endothelium-dependent relaxation, stimulate the production of superoxide, and examine the role of Ang II to enhance Rho-kinase–mediated smooth muscle contraction. Previously published effects of Ang II on the rodent vasculature have been vital for understanding basic AT1 receptor physiology. However, data gleaned from experiments in rodent models largely neglect the potential contribution of the different AT1 subtypes because the subtypes cannot be distinguished pharmacologically. This study on AT1A–/– mice investigated for the first time the effects of a gene-targeted deletion of the AT1A receptor on vascular relaxation and contraction, superoxide levels, and Rho-kinase signaling. The findings of the present study support a major role for AT1A in mediating Ang II–induced endothelial dysfunction and increased 5-HT contractility. Surprisingly, these effects appear to be independent of reactive oxygen species and RhoA/Rho kinase-signaling pathways.
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Acknowledgments |
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This work was supported by National Institutes of Health grants HL-48058, HL-61446, HL-38901, NS-24621, and HL-62984 (to C.D.S. and F.M.F.). Dr Ryan is the recipient of an American Heart Association Beginning Grant-In-Aid (0460046Z). Dr Didion is the recipient of an American Heart Association National Scientist Development Award (0230327N). We gratefully acknowledge the generous research support of the Roy J. Carver Trust. We thank Pamela Tompkins for technical assistance with the hydroethidine assay and Deborah R. Davis for technical assistance with osmotic pump implantation.
Received December 4, 2003; first decision January 8, 2004; accepted February 6, 2004.
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S. P. Didion, C. M. Lynch, and F. M. Faraci Cerebral vascular dysfunction in TallyHo mice: a new model of Type II diabetes Am J Physiol Heart Circ Physiol, March 1, 2007; 292(3): H1579 - H1583. [Abstract] [Full Text] [PDF]
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H. Girouard, L. Park, J. Anrather, P. Zhou, and C. Iadecola Cerebrovascular Nitrosative Stress Mediates Neurovascular and Endothelial Dysfunction Induced by Angiotensin II Arterioscler. Thromb. Vasc. Biol., February 1, 2007; 27(2): 303 - 309. [Abstract] [Full Text] [PDF]
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 M. J. Ryan and G. R. McLemore Jr. Hypertension and impaired vascular function in a female mouse model of systemic lupus erythematosus Am J Physiol Regulatory Integrative Comp Physiol, February 1, 2007; 292(2): R736 - R742. [Abstract] [Full Text] [PDF]
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 H. Ohtsu, H. Suzuki, H. Nakashima, S. Dhobale, G. D. Frank, E. D. Motley, and S. Eguchi Angiotensin II Signal Transduction Through Small GTP-Binding Proteins: Mechanism and Significance in Vascular Smooth Muscle Cells Hypertension, October 1, 2006; 48(4): 534 - 540. [Full Text] [PDF]
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 L. M. Harrison-Bernard, C. J. Monjure, and B. J. Bivona Efferent arterioles exclusively express the subtype 1A angiotensin receptor: functional insights from genetic mouse models Am J Physiol Renal Physiol, May 1, 2006; 290(5): F1177 - F1186. [Abstract] [Full Text] [PDF]
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H. Girouard, L. Park, J. Anrather, P. Zhou, and C. Iadecola Angiotensin II Attenuates Endothelium-Dependent Responses in the Cerebral Microcirculation Through Nox-2-Derived Radicals Arterioscler. Thromb. Vasc. Biol., April 1, 2006; 26(4): 826 - 832. [Abstract] [Full Text] [PDF]
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S. P. Didion, D. A. Kinzenbaw, and F. M. Faraci Critical Role for CuZn-Superoxide Dismutase in Preventing Angiotensin II-Induced Endothelial Dysfunction Hypertension, November 1, 2005; 46(5): 1147 - 1153. [Abstract] [Full Text] [PDF]
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S. Wesseling, D. A. Ishola Jr., J. A. Joles, H. A. Bluyssen, H. A. Koomans, and B. Braam Resistance to oxidative stress by chronic infusion of angiotensin II in mouse kidney is not mediated by the AT2 receptor Am J Physiol Renal Physiol, June 1, 2005; 288(6): F1191 - F1200. [Abstract] [Full Text] [PDF]
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 W. G. Barnes, E. Reiter, J. D. Violin, X.-R. Ren, G. Milligan, and R. J. Lefkowitz {beta}-Arrestin 1 and G{alpha}q/11 Coordinately Activate RhoA and Stress Fiber Formation following Receptor Stimulation J. Biol. Chem., March 4, 2005; 280(9): 8041 - 8050. [Abstract] [Full Text] [PDF]
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J. Vazquez, M. F. C. de Adjounian, C. Sumners, A. Gonzalez, C. Diez-Freire, and M. K. Raizada Selective Silencing of Angiotensin Receptor Subtype 1a (AT1aR) by RNA Interference Hypertension, January 1, 2005; 45(1): 115 - 119. [Abstract] [Full Text] [PDF]
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