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(Hypertension. 1996;28:104-108.)
© 1996 American Heart Association, Inc.

Articles

Angiotensin-(1-7) Inhibits Vascular Smooth Muscle Cell Growth

Ernest J. Freeman; Guy M. Chisolm; Carlos M. Ferrario; E. Ann Tallant

the Calhoun Research Laboratory, Department of Internal Medicine, Akron (Ohio) General Medical Center (E.J.F.); the Department of Cell Biology, The Research Institute of the Cleveland (Ohio) Clinic Foundation (G.M.C.); and the Hypertension Center, The Bowman Gray School of Medicine of Wake Forest University, Winston-Salem, NC (C.M.F., E.A.T.).

Correspondence to E. Ann Tallant, The Hypertension Center, The Bowman Gray School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157-1032.

	Abstract

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Although angiotensin II (Ang II) and the heptapeptide Ang-(1-7) differ by only one amino acid, the two peptides produce different responses in vascular smooth muscle cells. We previously showed that Ang II stimulated phosphoinositide hydrolysis, whereas Ang II and Ang-(1-7) released prostaglandins. We now report that Ang II and Ang-(1-7) differentially modulate rat aortic vascular smooth muscle cell growth. Ang-(1-7) inhibited [³H]thymidine incorporation in response to stimulation by fetal bovine serum, platelet-derived growth factor, or Ang II. The reduction in serum-stimulated thymidine incorporation by Ang-(1-7) depended on the concentration of the heptapeptide over the range of 1 nmol/L to 1 µmol/L, with a maximal inhibition of 60% by 1 µmol/L Ang-(1-7). Ang-(1-7) also inhibited the serum-stimulated increase in cell number to a maximum of 77% by 1 µmol/L Ang-(1-7). The attenuation of serum-stimulated thymidine incorporation by Ang-(1-7) was unaffected by antagonists selective for angiotensin type 1 (AT₁) or type 2 (AT₂) receptors; however, [Sar¹,Ile⁸]Ang II and [Sar¹,Thr⁸]Ang II were effective antagonists, indicating that growth inhibition by Ang-(1-7) was a result of angiotensin receptor activation. In contrast, Ang II stimulated [³H]thymidine incorporation in cultured vascular smooth muscle cells over the same concentration range, with a maximal stimulation of 314% at 1 µmol/L Ang II. Ang II also increased the total number of cells (to 145% of control), suggesting that enhanced thymidine incorporation was associated with vascular smooth muscle cell proliferation. The AT₁ antagonist losartan or L-158,809 but not AT₂ antagonists blocked [³H]thymidine incorporation by Ang II. These results suggest that Ang-(1-7) and Ang II exhibit opposite effects on the regulation of vascular smooth muscle cell growth. The inhibition of proliferation by Ang-(1-7) appears to be mediated by a novel angiotensin receptor that is not inhibited by AT₁ or AT₂ receptor antagonists.

Key Words: angiotensin-(1-7) • angiotensin II • receptors, angiotensin II • muscle, smooth, vascular • growth

	Introduction

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New studies implicate the heptapeptide Ang-(1-7) as a member of the family of angiotensin peptides contributing to the regulation of arterial pressure and body fluid volumes.^{1 2 3 4} Ang-(1-7) is produced from Ang I or Ang II by specific endopeptidases circulating in blood or present in the vascular endothelium, kidney, and brain parenchyma.^{5 6 7} Recent studies identified Ang-(1-7) as the major product generated from Ang I in VSM cells from SHR and Wistar-Kyoto rats.⁸ The enzyme responsible for the formation of Ang-(1-7) in VSM cells was characterized as metalloendopeptidase 24.15 (EC 3.4.24.15; thimet oligopeptidase).⁸

Moriguchi et al⁹ and Nakamoto et al¹⁰ proposed that Ang-(1-7) counterbalances the pressor actions of Ang II. This interpretation is based on two major lines of evidence. First, Ang-(1-7) stimulated prostaglandin release in cultured cells,^{11 12 13 14 15} whereas indomethacin abolished the vasodilator effect of Ang-(1-7) in rats¹⁶ and piglet pial arterioles.¹⁷ Second, systemic administration of Ang-(1-7) produced antihypertensive effects in SHR,¹⁸ in (mRen-2)27 transgenic hypertensive rats,⁹ and in the acquired form of canine renovascular hypertension.¹⁰ Additional evidence suggests that the vasodilator actions of Ang-(1-7) may involve increased production of nitric oxide. The depressor response produced by Ang-(1-7) in dogs with renovascular hypertension was attenuated after chronic inhibition of nitric oxide synthase,¹⁰ whereas the vasorelaxation produced by Ang-(1-7) in porcine¹⁹ and canine²⁰ coronary arteries was abolished by administration of the nitric oxide synthase inhibitor N^G-nitro-L-arginine methyl ester. In agreement with these studies, Osei et al²¹ showed that the vasodilator response produced by Ang-(1-7) in feline mesenteric and hindlimb vascular beds was prevented by pretreatment with N^G-nitro-L-arginine methyl ester. These data clearly demonstrated that Ang-(1-7) may act as an endogenous inhibitor of the vasoconstrictor actions of Ang II.

Numerous studies suggest that Ang II may play an important part in the pathogenesis of cardiac and vascular hypertrophy by mechanisms that are independent of the increased pressure load.^{22 23 24} In addition, it has been suggested that neointimal formation after balloon injury of rat arteries may be attenuated by ACE inhibitors and the AT₁ receptor antagonist losartan.^{25 26} The demonstration that these treatments are associated with significant increases in plasma and tissue concentrations of Ang-(1-7)^{27 28} led us to ask whether this novel member of the angiotensin peptide family may possess antiproliferative activities. With this in mind, we investigated the effect of Ang-(1-7) on the growth of rat thoracic aortic VSM cells.

	Methods

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Cell Culture Procedures
VSM cells were isolated from the thoracic aorta of 10- to 12-week-old male Sprague-Dawley rats (Harlan Sprague Dawley Inc, Indianapolis, Ind) by the procedure of explant culture described previously.²⁹ Cells were seeded in Dulbecco's modified Eagle's medium/Ham's F-12 (1:1) (JRH Biosciences) supplemented with 10% FBS (BioWhittaker Inc), 100 µg/mL penicillin, and 100 U/mL streptomycin (GIBCO). Cell preparations were kept at 37°C in a humidified atmosphere of 5% CO₂ and 95% room air. Culture purity was assessed by immunofluorescent staining with a monoclonal antibody specific for smooth muscle -actin (Sigma Chemical Co) followed by an anti-mouse fluorescein-conjugated goat IgG fraction (Organon Teknika Corp). Cells between passages 4 and 10 were used for all experiments.

Measurement of Thymidine Incorporation
We measured the incorporation of tritiated thymidine by VSM cells growing in 24-well culture plates. Cells were plated at a density of 2000 cells per well. Subconfluent monolayers were made quiescent by the removal of FBS from the incubation medium for 48 hours. Monolayers were then treated for 48 hours in the presence and absence of various angiotensin peptides, receptor antagonists, or mitogens. During the last 24 hours, 0.25 µCi of [³H]thymidine per milliliter culture medium was added to the growth medium. The incorporation of [³H]thymidine was determined after precipitation of acid-insoluble material with ice-cold 5% trichloroacetic acid. The acid-insoluble material was dissolved in 0.25N NaOH and counted in a liquid scintillation spectrometer in the presence of 5 mL Ecolite.

Measurement of Cell Number
The number of cells per well of a 24-well cluster dish was measured by cell counts. Confluent monolayers, made quiescent by 48-hour treatment with serum-free medium, were treated for 48 hours with either Ang II or Ang-(1-7) in the presence of 1% FBS. The cell monolayer was subsequently removed by treatment with trypsin/EDTA and immediately analyzed with a Cell Counter-channelyser ZM (Coultronics) equipped with a 140-µm aperture orifice tube.

Materials
[³H]Thymidine (20 Ci/mmol) was obtained from Amersham. Ang II, Ang-(1-7), [Sar¹,Thr⁸]Ang II, and [Sar¹,Ile⁸]Ang II were obtained from Bachem California. Human recombinant PDGF-BB was from GIBCO BRL. Losartan potassium was a kind gift from Dr P. Timmermans of DuPont; L-158,809 was from Merck Inc Research Laboratories; CGP 42112A was a kind gift from Dr M. deGasparo of CIBA-Geigy; and PD 123177 was obtained from Parke-Davis.

Statistical Analysis
All data are expressed as mean±SE. Data were analyzed by Student's t tests corrected for multiple comparisons by the Bonferroni method. The criterion for statistical significance was a value of P<.05.

	Results

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Opposing Effects of Ang-(1-7) and Ang II on VSM Cell Growth
For determination of the effect of Ang-(1-7) on VSM cell growth, subconfluent monolayers of rat aortic VSM cells, made quiescent by removal of serum from their growth medium for 48 hours, were incubated in the presence or absence of 1 µmol/L Ang-(1-7) for 48 hours. Cells were treated with Ang-(1-7) under basal conditions in the absence of a mitogen or in the presence of 1% FBS, 5 ng/mL PDGF, or 100 nmol/L Ang II. During the last 24 hours, [³H]thymidine was added to the growth medium for detection of changes in the level of DNA synthesis.

The amount of [³H]thymidine incorporation was increased by treatment with FBS (to 223±25% of basal), PDGF (to 389±36% of basal), or Ang II (to 182±4.5% of control) (Fig 1). In the presence of Ang-(1-7), [³H]thymidine incorporation in response to FBS, PDGF, and Ang II was significantly attenuated. The same Ang-(1-7) concentration also reduced significantly the amount of [³H]thymidine incorporation into VSM cells maintained under serum-free conditions. Although cells were made quiescent by 48-hour pretreatment under serum-free conditions, we observed a small increase in [³H]thymidine incorporation after a subsequent 48 hours in serum-free medium, suggesting that a small number of cells escaped from the quiescent state (data not shown). However, Ang-(1-7) had no effect on the amount of [³H]thymidine incorporation into VSM cells maximally stimulated by treatment with 10% FBS (data not shown), suggesting that Ang-(1-7) inhibited VSM cell growth only under conditions of submaximal growth stimulation.

View larger version (30K): [in this window] [in a new window]   Figure 1. Effect of Ang-(1-7) on mitogen-stimulated [3H]thymidine incorporation into VSM cells. Cells made quiescent by 48 hours of incubation in serum-free medium were either cultured for an additional 48 hours under serum-free conditions (basal) or treated with 1% FBS, 5 ng/mL PDGF, or 100 nmol/L Ang II under control conditions (in the absence of peptide) or in the presence of 1 µmol/L Ang-(1-7). Thymidine incorporation was measured as described in "Methods" and is presented as percentage of basal. Data were obtained from duplicate experiments of VSM cells obtained from at least three different rats. Results are presented from three different sets of VSM cells. Basal [3H]thymidine incorporation was 31 217±228 cpm per well for the effect of Ang-(1-7) under basal conditions or FBS stimulation, 4052±691 for stimulation by PDGF, and 1222±40 for stimulation by Ang II. *P<.05, cells treated with Ang-(1-7) compared with control under the same conditions.

Inhibition of serum-stimulated thymidine incorporation by Ang-(1-7) was concentration dependent over the range of 1 nmol/L to 1 µmol/L, with a reduction to 39.7% of control at the maximal dose of 1 µmol/L Ang-(1-7) (Fig 2, top). The EC₅₀ for inhibition of serum-stimulated thymidine incorporation by Ang-(1-7) was 115.4 nmol/L. Ang-(1-7) concentrations greater than 1 µmol/L caused no additional decrease in [³H]thymidine incorporation.

View larger version (30K): [in this window] [in a new window]   Figure 2. Effect of Ang II and Ang-(1-7) on [3H]thymidine incorporation into VSM cells. Cells made quiescent by 48 hours in serum-free medium were treated for an additional 48 hours with either Ang-(1-7) in the presence of 1% FBS (top) or Ang II (bottom). Thymidine incorporation was measured as described in "Methods." Results are from four experiments in duplicate. Top, Inhibition of FBS-stimulated [3H]thymidine incorporation by increasing concentrations of Ang-(1-7) is presented as percentage of serum-stimulated activity (29 442±3253 cpm per well). Bottom, Stimulation of [3H]thymidine incorporation by increasing concentrations of Ang II is presented as percentage of basal activity (13 217±228 cpm per well).

As a comparison, cultured VSM cells were also exposed to Ang II concentrations ranging from 1 nmol/L to 1 µmol/L. Addition of Ang II caused a concentration-dependent increase in [³H]thymidine incorporation, with an EC₅₀ of 17.9 nmol/L (Fig 2, bottom). At a maximal dose of 1 µmol/L, Ang II increased thymidine incorporation by 314% above control. Ang II concentrations greater than 1 µmol/L caused no additional increase in [³H]thymidine incorporation.

To determine whether the alterations in [³H]thymidine incorporation by angiotensin peptides were associated with cell growth, we measured the effect of Ang-(1-7) and Ang II on cell number. The Table shows that Ang-(1-7) caused a concentration-dependent decrease in serum-stimulated cell growth. Although 100 nmol/L of the heptapeptide caused only a slight decrease in serum-stimulated cell growth, 1 µmol/L Ang-(1-7) decreased the total number of cells in individual wells to 77% of the number of cells in wells stimulated with serum. In contrast, the total number of cells in individual wells of a 24-well cluster plate was stimulated 45% above basal by 1 µmol/L Ang II.

View this table: [in this window] [in a new window]   Table 1. Effect of Angiotensin Peptides on Cell Number

Diversity of Receptors Mediating [³H]Thymidine Incorporation by Ang II and Ang-(1-7)
The Ang II receptor subtype involved in the inhibition of serum-stimulated [³H]thymidine incorporation by Ang-(1-7) was determined with subtype-selective AT₁ and AT₂ receptor antagonists. Serum-stimulated VSM cells were exposed to 1 µmol/L Ang-(1-7) after pretreatment with a 10-fold molar excess of subtype-selective and nonselective Ang II receptor antagonists (Fig 3, top). Neither a 10-fold molar excess of the AT₁ antagonist L-158,809 or the AT₂ antagonists PD 123177 or CGP 42112A reversed the Ang-(1-7) inhibition of serum-stimulated thymidine incorporation. On the other hand, 10 µmol/L [Sar¹,Thr⁸]Ang II or [Sar¹,Ile⁸]Ang II effectively reduced the antimitogenic effect of Ang-(1-7), suggesting that Ang-(1-7) was coupled to a novel angiotensin receptor. In contrast, the increase in [³H]thymidine incorporation by 1 µmol/L Ang II was markedly attenuated by pretreatment with either of the two AT₁ receptor antagonists, losartan or L-158,809 (10 µmol/L) (Fig 3, bottom). Indeed, [³H]thymidine incorporation by Ang II was significantly reduced below basal levels in the presence of AT₁ receptor blockade. The Ang II-mediated incorporation of [³H]thymidine was not inhibited by a 10 µmol/L concentration of the AT₂ antagonists PD 123177 or CGP 42112A. Treatment of VSM cells with 10 µmol/L of any of the antagonists alone had no effect on the basal level of thymidine incorporation.

View larger version (41K): [in this window] [in a new window]   Figure 3. Effect of receptor antagonists on [3H]thymidine incorporation into VSM cells in response to angiotensin peptides. Cells made quiescent by 48 hours in serum-free medium were pretreated for 5 minutes with 10 µmol/L losartan potassium, L-158,809, PD 123177, CGP 42112A, [Sar1,Thr8]Ang II (Sarthran), or [Sar1,Ile8]Ang II. Thymidine incorporation was measured as described in "Methods" and is presented as cpmx10-3 per well. Results are from four experiments in duplicate. *P<.05 compared with [3H]thymidine incorporation in response to 1% FBS (top) or under basal conditions (bottom). Top, Individual wells were treated with either 1% FBS or 1% FBS and 1 µmol/L Ang-(1-7) after pretreatment with the indicated antagonist. Bottom, Individual wells were either not treated (basal) or treated with 1 µmol/L Ang II after pretreatment with the indicated antagonist.

	Discussion

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Ang-(1-7) caused an antiproliferative response in cultured VSM cells, inhibiting mitogen-stimulated [³H]-thymidine incorporation and reducing serum-stimulated cell growth. In contrast, Ang II caused an increase in [³H]thymidine incorporation in cultured VSM cells, as previously reported by other researchers.^{30 31 32 33 34} Although altered thymidine incorporation also occurs in hypertrophic responses, the decrease in cell number produced by Ang-(1-7) and the increased cell number in response to Ang II indicate that the peptides modulate cell growth. Growth inhibition by Ang-(1-7) was prevented by the sarcosine antagonists of Ang II, [Sar¹,Ile⁸]Ang II and [Sar¹,Thr⁸]Ang II. However, neither the AT₁ antagonist L-158,809 nor the AT₂ antagonists PD 123177 or CGP 42112A blocked the effect of Ang-(1-7). These data suggest that growth inhibition by Ang-(1-7) was coupled to a non-AT₁, non-AT₂ angiotensin receptor. These experiments provide the first evidence for opposing actions of Ang II and Ang-(1-7) in VSM cell growth.

Ang-(1-7) significantly reduced serum-stimulated [³H]-thymidine incorporation, with maximal inhibition by 1 µmol/L Ang-(1-7) to 39.7% of control. The EC₅₀ for growth stimulation by Ang II was 17.9 nmol/L, similar to the values previously reported by other researchers.^{33 34 35} In contrast, the EC₅₀ for growth inhibition by Ang-(1-7) was 115.4 nmol/L, a value 6.4 times higher than the EC₅₀ for Ang II growth stimulation. Although circulating levels of Ang-(1-7) may be lower than those of Ang II in the rat, we²⁸ and others³⁶ showed a 6- to 10-fold rise in plasma Ang-(1-7) concentrations after long-term treatment with ACE inhibitors. The same treatments are associated with a fall in Ang II plasma levels. From the data reported by Campbell et al,³⁶ it can be calculated that the level of Ang-(1-7) is 6.4-fold higher than the level of Ang II after treatment of Sprague-Dawley rats with ramipril. Similar increases in Ang-(1-7) levels after ACE inhibitor treatment were observed in both Wistar-Kyoto rats and SHR.²⁸ These results suggest that Ang-(1-7) may participate in the antiproliferative effects of ACE inhibitors after endothelial injury.^{25 26}

Our studies did not investigate the nature of the second-messenger system mediating the inhibition of [³H]thymidine incorporation by Ang-(1-7) other than demonstrating that the effect is produced by the binding of the peptide to a site that is not competed for by AT₁ or AT₂ subtype-selective receptor antagonists. In previous studies, we showed that Ang-(1-7) released prostaglandins from VSM cells.^{13 14} Since Uehara et al³⁷ found that prostaglandins I₂, E₂, and D₂ inhibited VSM cell growth, Ang-(1-7) may inhibit VSM cell growth through prostaglandin production. Future experiments are necessary for determination of the mechanism for growth inhibition by Ang-(1-7).

Growth stimulation in response to Ang II was coupled to an AT₁ receptor, in agreement with previous studies.^{31 34 38 39} The increase in [³H]thymidine incorporation by Ang II was prevented by the selective AT₁ receptor antagonists losartan and L-158,809. In addition, Ang II caused a decrease in thymidine incorporation when growth stimulation coupled to an AT₁ receptor was blocked. These results are in agreement with studies suggesting that Ang II may both stimulate and inhibit VSM cell growth.²² Ang II also inhibited incorporation of [³H]thymidine into cultured rat coronary artery endothelial cells in the presence of losartan.⁴⁰ In addition, a recent report by Nakajima et al⁴¹ showed that Ang II inhibited the growth of VSM cells transfected with the AT₂ receptor, whereas overexpression of the AT₂ receptor in the balloon-injured rat carotid artery attenuated neointimal formation. These results suggest that Ang II may be antiproliferative when Ang II receptors coupled to growth stimulation are selectively blocked with AT₁ receptor antagonists.

In a normal uninjured blood vessel, the rate of growth of vascular cells is balanced by factors released from both VSM and endothelial cells. In contrast, after angioplasty or in atherosclerosis and hypertension, VSM cells proliferate, migrate into the neointima, and form extracellular matrices that lead to vascular stenosis. We propose that this results from an imbalance in the ratio of growth-stimulatory to growth-inhibitory factors. ACE inhibitors and the AT₁ antagonist losartan prevented neointimal proliferation in rats after balloon catheterization injury.^{25 26} Inhibition of the growth-stimulatory effects of Ang II at AT₁ receptors most likely participates in the antiproliferative effects of both ACE inhibitors and losartan. However, since plasma levels of Ang-(1-7) are increased after treatment with ACE inhibitors or losartan,^{27 28} the growth-inhibitory effects of ACE inhibitors and losartan may also result from inhibition of VSM cell growth by elevated levels of Ang-(1-7). On the basis of the results of the present study, we suggest that Ang-(1-7) counterregulates the growth-stimulatory properties of Ang II by directly inhibiting the proliferation of VSM cells.

	Selected Abbreviations and Acronyms

 

ACE = angiotensin-converting enzyme Ang I, II = angiotensin I, II Ang-(1-7) = angiotensin-(1-7) AT1, AT2 = angiotensin type 1, type 2 FBS = fetal bovine serum PDGF = platelet-derived growth factor SHR = spontaneously hypertensive rat(s) VSM = vascular smooth muscle

	Acknowledgments

 
This work was supported by a Fellowship from the American Heart Association (AHA), Northeast Ohio Affiliate (E.J.F.); a Grant-in-Aid from the AHA, Ohio Affiliate (E.J.F.); grants NS-31664 (E.A.T.), HL-47852 (G.M.C.), and HL-50066 (C.M.F., E.A.T.) from the National Institutes of Health; and a Losartan Medical School Grant from Merck Inc (C.M.F., E.A.T.).

	Footnotes

 
Presented in part at the 1993 Meeting of the Council for High Blood Pressure Research, September 28 to October 1, 1993, San Francisco, Calif.

Received October 30, 1995; first decision January 9, 1996; first decision March 19, 1996;

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