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(Circulation Research. 2001;89:930.)
© 2001 American Heart Association, Inc.

Integrative Physiology

Inhibition of Transforming Growth Factor-ß Signaling Accelerates Atherosclerosis and Induces an Unstable Plaque Phenotype in Mice

Ziad Mallat, Andrea Gojova, Carmen Marchiol-Fournigault, Bruno Esposito, Caroline Kamaté, Régine Merval, Didier Fradelizi, Alain Tedgui

From the Institut National de la Santé et de la Recherche Médicale (Z.M., A.G., B.E., R.M., A.T.), INSERM U541, Institut Fédératif de Recherche "Circulation Paris 7," Hôpital Lariboisière; and ICGM-INSERM U477, Hôpital Cochin (C. M.-F., C.K., D.F.), Paris, France.

Correspondence to Ziad Mallat, MD, PhD, INSERM U541, Hôpital Lariboisière, 41 Bd de la chapelle, 75010 Paris, France. E-mail ziad.mallat{at}inserm.lrb.ap-hop-paris.fr

	Abstract

Top Abstract Introduction Materials and Methods Results Discussion References

 
Abstract—— Atherosclerosis is a disease of the arterial wall that seems to be tightly modulated by the local inflammatory balance. Whereas a large body of evidence supports a role for proinflammatory mediators in disease progression, the understanding of the role of the antiinflammatory component in the modulation of plaque progression is only at its beginning. TGF-ß1, -ß2, and -ß3 are cytokines/growth factors with broad activities on cells and tissues in the cardiovascular system and have been proposed to play a role in the pathogenesis of atherosclerosis. However, no study has examined the direct role of TGF-ß in the development and composition of advanced atherosclerotic lesions. In the present study, we show that inhibition of TGF-ß signaling using a neutralizing anti–TGF-ß1, -ß2, and -ß3 antibody accelerates the development of atherosclerotic lesions in apoE-deficient mice. Moreover, inhibition of TGF-ß signaling favors the development of lesions with increased inflammatory component and decreased collagen content. These results identify a major protective role for TGF-ß in atherosclerosis.

Key Words: atherosclerosis • cytokines • inflammation • macrophages • lymphocytes

	Introduction

Top Abstract Introduction Materials and Methods Results Discussion References

 
Atherosclerosis has been recognized as an inflammatory disease of the arterial wall.¹ Endothelial activation by oxidized lipoproteins plays an important role in the initiation of the atherosclerotic lesion through increased adhesion of mononuclear cells and their recruitment into the vascular wall.¹ The recruited inflammatory cells produce and induce the expression of numerous inflammatory cytokines and chemokines, promoting lesion progression. Enhanced accumulation of lipids and inflammatory cells and production of extracellular matrix by the intimal smooth muscle cells (SMCs) participate in the formation of advanced lesions. The inflammatory response also determines plaque composition and, as a result, strongly contributes to the occurrence of plaque complications that are responsible for clinically severe acute ischemic syndromes.² Recent studies suggest that antiinflammatory cytokines with deactivating properties on macrophages and/or T cells are produced within the atherosclerotic lesion.^3,4 Among the antiinflammatory cytokines, interleukin (IL)-10 plays a critical role in the regulation of the inflammatory balance⁴ and greatly determines lesion development.^5,6 However, antiinflammatory cytokines differ in their effects on inflammatory and vascular cells, and may therefore differentially affect atherosclerotic plaque development and composition. For example, the Th2 antiinflammatory cytokine IL-4 has been shown to enhance the formation of heat shock protein-induced lipid lesions.⁷ Apart from IL-10, no other antiinflammatory cytokine with protective effects on both lesion development and stability has been identified. TGF-ß1, a widely expressed cytokine, is produced by both inflammatory and vascular cells and expressed in human and mouse atherosclerotic plaques.^8,9 TGF-ß1 was first identified as an antiinflammatory cytokine.¹⁰ These antiinflammatory properties suggest a potential antiatherogenic role. In agreement with this hypothesis, Grainger et al¹¹ recently showed increased endothelial activation and macrophage infiltration in aortic sinus of TGF-ß1 heterozygous mice fed a cholate-supplemented atherogenic diet. However, no study has already examined the direct role of TGF-ß on the development or the composition of advanced atherosclerotic lesions. This issue is important given the contradictory roles ascribed to TGF-ß in the pathogenesis of atherosclerosis.^8,11–18 Therefore, the aim of the present study was to examine the role of TGF-ß signaling in the development of atherosclerosis in apoE knockout mice that are known to spontaneously develop human-like lesions when fed a chow diet. To this end, TGF-ß1, -ß2, and -ß3 activity was inhibited by treatment of mice with a neutralizing anti–TGF-ß antibody. Moreover, we performed a detailed study of plaque composition in order to define the mechanisms of action of TGF-ß and its potential role on plaque stability.

	Materials and Methods

Top Abstract Introduction Materials and Methods Results Discussion References

 
Mice
Thirty one male C57BL/6J apoE-deficient mice (Transgenic Alliance, France) were obtained at 6 weeks of age and were placed on a chow diet containing 3% fat (UAR) with free access to food and water. Mice were kept in accordance with standard animal care requirements, housed 5 to 6 per cage, and maintained on a 12-hour light-dark cycle. The mice were housed under conventional conditions.

In Vivo Treatment of Animals With Antibody
Mice were injected intraperitoneally in a volume of 240 µL with either the anti–hTGF-ß1, -ß2, -ß3 2G7 monoclonal antibody (mAb) (ascitic fluid at 1:10 dilution) (17 mice),^19,20 or an isotype matched (IgG2b) irrelevant antihuman cytotrophoblast JEG13 mAb (ascitic fluid at 1:10 dilution) (14 mice). Injections were repeated once a week for 9 weeks. Such 2G7 mAb dilution was selected from in vitro preliminary testing, which indicated that 50 µL of anti–TGF-ß 2G7 mAb ascitic fluid at 1:800 dilution neutralized 50% of the biological activity of 0.1 ng purified TGF-ß1 (inhibition of IL-5–induced proliferation of the erythroleukemia cell line, TF-1 in vitro).²¹ The control JEG13 mAb was devoid of neutralizing activity. In an additional series of experiments, we determined TGF-ß1 activity in plasma samples obtained during the first week of treatment from both groups of mice using the same methodology.

Tissue Preparation and Morphometric Analysis
At 15 weeks of age, mice were anesthetized by isoflurane inhalation. Blood was drawn from the retroorbital venous plexus, and plasma cholesterol and HDL were measured with a commercially available cholesterol kit (Sigma). The anesthetized mice were killed by CO₂ overdose. The basal half of the ventricles and the ascending aorta were perfusion-fixed in situ with 4% paraformaldehyde. After then, they were removed, transferred to a PBS-30% sucrose solution, embedded in frozen OCT and stored at -70°C. Serial 8 to 10-µm sections of the aortic sinus with valves (60 to 80 per mouse) were cut on a cryostat. Of every 5 sections, one was kept for detection of lipid deposition with Oil red; the other sections were dedicated to immunohistological analysis and collagen detection.

Collagen fibers were stained with Sirius red. Morphometric analysis was performed with an automated image processor (NS 15000, Microvision). The lesion collagen content was determined by measuring the relative area/density in 12 contiguous fields in each Sirius red–stained section.

Immunohistochemical Analysis
Immunohistochemical analysis was performed, as previously described.⁶ The following primary antibodies were used: a primary rat monoclonal antibody against mouse macrophages, clone MOMA-2 at a dilution 1:10 (BioSource International), a primary rabbit anti-CD3 antibody at a dilution 1:400 (Dako), an alkaline phosphatase-conjugated primary mouse monoclonal antibody against -actin at a dilution 1:30 (Sigma), a primary goat polyclonal anti–VCAM-1 antibody at a dilution 1:40 (Santa Cruz), a primary rabbit polyclonal antibody against phosphorylated Smad2 at 20 µg/mL (Upstate Biotechnology), a primary rabbit polyclonal anti–TGF-ß1 antibody at 10 µg/mL (Santa Cruz), a primary rat horseradish peroxidase-conjugated monoclonal antibody against mouse IgG2b (Zymed), and a primary mouse monoclonal antibody directed against NF-B, p65 subunit at a dilution 1:200 (Roche). This latter antibody recognizes the IB binding region on the p65 DNA binding subunit and, therefore, selectively reacts with p65 in the activated form of NF-B. Immunostains were visualized after incubation with the corresponding preadsorbed secondary biotinylated antibodies (Vector Laboratories) and the use of avidin-biotin horseradish peroxidase visualization systems (Vectastain ABC kit, Vector Laboratories). The conjugated -actin antibody was visualized after addition of a substrate for alkaline phosphatase (NBT/BCIP). We took advantage of the InnoGenex mouse-to-mouse iso-IHC kit to perform a specific primary antibody biotinylation and to abrogate any background staining that may result from the use of the mouse primary anti–NF-B antibody on mouse tissues. Irrelevant immunoglobulins were used for negative controls. At least four sections per animal were analyzed for each immunostaining. Morphometric analysis was performed as described.

Statistical Analysis
The effects of the anti–TGF-ß and control antibodies on lesion area and plaque composition were compared using a t test. Data are expressed as mean±SEM. A value of P<0.05 was considered to be statistically significant.

	Results

Top Abstract Introduction Materials and Methods Results Discussion References

 
In order to examine the role of endogenous TGF-ß signaling in atherosclerosis, mice were treated with either a neutralizing anti–TGF-ß mAb or an irrelevant mAb. Treatment with anti–TGF-ß mAb resulted in both systemic and local TGF-ß neutralization. Plasma from mice treated with anti–TGF-ß 2G7 mAb at a dilution of 1:40 neutralized 33.3±2.7% of the biological activity of TGF-ß1 in the TF-1 assay at day 2, 40.2±1.5% at day 4, and 26.2±7.7% at day 7. Plasma from mice treated with the control JEG13 mAb had no neutralizing activity. To assess the in vivo tissue activity of the anti–TGF-ß antibody, we determined the expression of TGF-ß1 and that of phosphorylated Smad2 by use of specific antibodies. Treatment with the anti–TGF-ß mAb did not decrease TGF-ß1 protein expression in the aortic sinus (14.8±3.5% versus 16.3±0.3% of plaque area in anti–TGF-ß–treated and control mice, respectively). Staining for phospho-Smad2 was detected in the aortic sinus of mice treated with the irrelevant mAb (Figure 1). However, treatment with the anti–TGF-ß antibody abolished Smad2 phosphorylation (Figure 1), indicating a potent in vivo inhibition of TGF-ß signaling. Moreover, in vivo administration of the anti–TGF-ß antibody for 9 weeks induced important proinflammatory changes in the myocardium. This is reflected by the important expression of the activated form of NF-B and the important infiltration of myocardium by T lymphocytes in all anti–TGF-ß–treated mice (P<0.0001) (Figure 2). These changes were not observed following 9 weeks of treatment with the irrelevant antibody and were not associated with detectable antibody deposition in the tissues (data not shown). In addition, the inflammatory response was not widespread because it was rarely observed in the liver of both groups of mice (data not shown). This pattern of inflammatory response is very similar to that reported in C57BL/6 TGF-ß1 knockout mice.^22,23

View larger version (111K): [in this window] [in a new window]   Figure 1. Representative photomicrograph showing staining for phosphorylated Smad2 (red) in fatty streaks of the aortic sinus of mice treated with the irrelevant antibody (a). Arrows indicate nuclear staining. Virtually no staining for phospho-Smad2 was detected in the aortic sinus of mice treated with the anti-TGF-ß antibody (b). Original magnification, x400.

View larger version (166K): [in this window] [in a new window]   Figure 2. Representative photomicrograph showing nuclear staining (red) for the activated form of NF-B in the myocardium of anti–TGF-ß–treated mice (b). Virtually no staining for NF-B was detected in the myocardium of mice treated with the irrelevant antibody (a). d shows an important infiltration of CD3-positive cells (red staining) in the myocardium of anti–TGF-ß–treated mice in comparison with the myocardium of control mice (c). Original magnification, x400.

Effect of Inhibition of TGF-ß Signaling on Atherosclerotic Lesion Size
At 15 weeks of age (9 weeks of antibody treatment), animal weights, total plasma cholesterol, and HDL cholesterol levels were not different between the two groups (Table 1). However, analysis of aortic sinus sections stained with Oil red revealed significant differences in lipid deposition and atherosclerotic plaque size (Figures 3a and 3b). Morphometric analysis showed that administration of the neutralizing anti–TGF-ß mAb for 9 weeks induced a significant 2-fold increase in lesion size compared with mice treated with the irrelevant mAb (82 215±9593 µm² versus 45 601±5803 µm², respectively, P<0.005) (Table 1). This finding underscores the natural protective role of TGF-ß against the development of atherosclerosis.

View this table: [in this window] [in a new window]   Table 1. Weights, Total, and HDL Plasma Cholesterol Levels in 15-Week-Old Male apoE-Deficient Mice Treated Once a Week for 9 Weeks With Either a Neutralizing Anti–TGF-ß mAb or an Irrelevant mAb

View larger version (134K): [in this window] [in a new window]   Figure 3. Representative photomicrographs showing atherosclerotic lesions in the aortic sinus of apoE-deficient mice treated with either a neutralizing anti–TGF-ß mAb (b and d) or an irrelevant mAb (a and c). In a and b, the sections were stained with Oil red. c and d show staining (red) with the antimacrophage antibody MOMA2. Sections were counterstained with hematoxylin and examined using light microscopy. Original magnifications, a and b, x40; c and d, x200.

Effect of Inhibition of TGF-ß Signaling on Atherosclerotic Lesion Composition
Analysis of atherosclerotic lesion composition revealed important differences between the 2 groups of mice in terms of cellular composition. Atherosclerotic lesions of anti–TGF-ß–treated mice showed a 57% increase in cellularity compared with the control mice (3745±309 cells/mm² versus 2379±510 cells/mm², respectively, P=0.03). As shown below, this was due to increased infiltration of inflammatory cells. Immunohistochemical studies and quantitative analysis showed no differences in -actin SMC positivity between the 2 groups. The expression of -actin in the intima of individual lesions was highly related to their size, with larger lesions showing SMC infiltration in the fibrous cap close to the lumen (data not shown). However, the percentage of lesion cross-sectional area occupied by macrophages (staining for MOMA-2) was significantly higher in anti–TGF-ß–treated mice than in control mice (69.0±3.3% versus 52.9±2.2%, respectively, P=0.002) (Figures 3c and 3d). The number of infiltrating lymphocytes increased with the size of the lesion and was therefore higher in mice treated with anti–TGF-ß. However, when expressed per lesion cross-sectional area, the number of CD3-positive cells was not statistically different between the 2 groups (520.3±76.3 T lymphocytes/mm² in mice treated with anti–TGF-ß versus 389.0±39.0 T lymphocytes/mm² in control mice, P=0.18). The increased infiltration of inflammatory cells in lesions of anti–TGF-ß–treated mice could not be ascribed to increased endothelial activation because VCAM-1 expression did not differ between the 2 groups (data not shown). However, such endothelial activation could have been more critical at an earlier stage of the disease. Interestingly, the close adventitial tissue (50 µm around the aortic sinus) of anti–TGF-ß–treated mice showed more than 3-fold increase in CD3-positive lymphocytes compared with the control mice (102.8±13.4 CD3+ cells versus 32.5±6.7 CD3+ cells per section per mouse, respectively, P=0.0003), indicating an important adventitial inflammation.

TGF-ß, especially TGF-ß1, is implicated in extracellular matrix remodeling and is known to be a potent fibrotic cytokine,²⁴ which may have an important impact on plaque collagen content and stability. Therefore, we determined the collagen content in the atheromatous lesions. Because collagen content may depend on the size of the lesion, only large lesions were examined for the presence of collagen by staining with Sirius red (Figure 4). Seventeen individual lesions of more than 20 000 µm² were identified in mice treated with the irrelevant mAb and were size-matched with 17 lesions in anti–TGF-ß–treated mice. Quantitative analysis of collagen content showed that collagen accumulation was significantly reduced in anti–TGF-ß–treated mice compared with the control mice (12.3±1.6% versus 26.8±3.0%, respectively, P=0.0002).

View larger version (76K): [in this window] [in a new window]   Figure 4. Representative photomicrographs showing atherosclerotic lesions in the aortic sinus of apoE-deficient mice treated with either a neutralizing anti–TGF-ß mAb (b) or an irrelevant mAb (a). Collagen content in the lesions was detected by staining with Sirius red. Seventeen individual lesions of more than 20 000 µm2 were identified in mice treated with the irrelevant mAb and were size-matched with 17 lesions in anti–TGF-ß–treated mice. *indicates the media; L denotes the lumen of the vessel.

	Discussion

Top Abstract Introduction Materials and Methods Results Discussion References

 
In the present study, we show that inhibition of TGF-ß signaling accelerates the development of atherosclerotic lesions in apoE-deficient mice and favors the development of lesions with increased inflammatory component and decreased collagen content. These results identify a major protective role for TGF-ß in atherosclerosis.

Atherosclerosis is a disease of the arterial wall that seems to be tightly modulated by the local inflammatory balance. In this study, we sought to examine the role of TGF-ß in the pathogenesis of atherosclerosis for several reasons. Besides its effects on cell cycle regulation and survival/apoptosis in many cell types including endothelial and smooth muscle cells,²⁵ TGF-ß functions as an antiinflammatory cytokine.²⁶ TGF-ß was first reported to be a deactivating factor of macrophages¹⁰ and also has potent antiinflammatory effects in vitro on vascular cells reducing cytokine-induced expression of chemokines and adhesion molecules.^27–31 The relevance of the in vitro findings to in vivo conditions is substantiated by the observation that TGF-ß1–deficient mice die in utero or in the perinatal period because of widespread uncontrolled inflammation.^22,23 These antiinflammatory properties suggest a potential antiatherogenic role for TGF-ß1. In agreement with this hypothesis, a recent study showed increased endothelial activation in TGF-ß1 +/- mice fed a cholate-containing fat diet.¹¹ Moreover, other studies showed negative correlation between TGF-ß1 activity/signaling and the extent of atherosclerosis.^17,32–34 However, these results have been challenged,^8,16 and more importantly, no direct causal relationship between TGF-ß activity and atherosclerosis was established in these studies. On the other hand, TGF-ß is also known to be an important fibrotic cytokine and plays a critical role in matrix remodeling enhancing collagen synthesis.²⁴ These effects have been proposed to favor matrix deposition and to increase lipoprotein trapping in the arterial intima,⁸ potentially leading to plaque growth and progression. In order to address directly the role of TGF-ß, we inhibited TGF-ß signaling in mice by repeated administration of the neutralizing 2G7 anti–TGF-ß mAb. Although TGF-ß1 protein expression was not affected, this strategy inhibited Smad2 phosphorylation and induced inflammatory changes in the myocardium of anti–TGF-ß–treated mice but not in mice treated with the irrelevant mAb. The inflammatory response was not widespread and was very similar to that reported in C57BL/6 mice deficient in TGF-ß1.²² Therefore, significant and specific inhibition of TGF-ß signaling was achieved in vivo using the present protocol. Our study clearly shows that this inhibition of TGF-ß signaling in mice susceptible to human-like atherosclerosis significantly accelerates lesion development, strongly suggesting an important protective role of endogenous TGF-ß activity against the development of atherosclerosis.

In order to begin to gain insight into the mechanisms responsible for the protective effect of TGF-ß, we performed detailed analysis of lesion composition. Atherosclerotic lesions of anti–TGF-ß–treated mice showed increased infiltration of inflammatory cells, particularly macrophages, and decreased collagen content compared with the lesions of control mice, suggesting a switch toward an unstable plaque phenotype. These plaque features are compatible with the deactivating properties of TGF-ß on inflammatory and vascular cells²⁶ and with the role of TGF-ß in matrix remodeling.²⁴ In contrast to a recent study,¹¹ we could not detect any effect of decreased TGF-ß activity on VCAM-1 expression using similar immunohistochemical techniques, suggesting no major role for this adhesion molecule in the effects of TGF-ß on plaque progression at this advanced stage of the disease. However, our results could not exclude a potential role of VCAM-1 or other adhesion molecules at an earlier stage of development. Moreover, we could not detect any effect of TGF-ß inhibition on smooth muscle -actin expression as previously suggested,¹¹ excluding an important role for this process in the protective effects of TGF-ß in atherosclerosis. Interestingly, we observed a 3-fold increase in lymphocyte infiltration in the adventitia in close contact with the vessel wall. The lymphocyte infiltration seems to precede lesion development because it was also observed subjacent to parts of the vessel wall that were not already affected by lipid infiltration. This important adventitial inflammation could significantly contribute to atherosclerotic plaque progression. Finally, it could be argued that the anti–TGF-ß antibody might stimulate an inflammatory reaction, through formation of immune complexes, independent of its neutralizing activity. However, antibody deposition in tissues was not directly related to the extent of the inflammatory reaction. As in C57BL/6 TGF-ß1 knockout mice,²² the inflammatory response observed in our anti–TGF-ß–treated mice was most important in the heart, where almost no antibody deposition was detected, and much less pronounced in the liver, despite significant antibody deposition. On the other hand, the inflammatory changes were closely related to inhibition of TGF-ß activity in the circulating blood and to inhibition of TGF-ß signaling in the aorta (inhibition of Smad2 phosphorylation). Therefore, we cannot rule out the possibility that both systemic and local inhibition of TGF-ß activity concurred to our results.

In conclusion, the present study shows that in vivo inhibition of TGF-ß signaling induces an unstable plaque phenotype and, therefore, points to an important protective role for endogenous TGF-ß in both plaque development and composition. This protective effect seems to depend on the potent deactivating effects of TGF-ß on macrophages and T lymphocytes and does not seem to be related to its effects on smooth muscle cell differentiation and/or accumulation. Further studies are needed to fully understand these important protective mechanisms and the role of each specific TGF-ß in this context.

	Acknowledgments

 
This work was supported by Action Concertée Incitative Jeunes Chercheurs, Ministère de la Recherche, France and by Fondation de France. We are grateful to the group of Dr Francis Bayard, INSERM U397, for providing us with the C57BL/6J apoE knockout mice.

Received May 29, 2001; revision received September 12, 2001; accepted September 19, 2001.

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