This Article Abstract Full Text (PDF) All Versions of this Article: 89/10/930    most recent hh2201.099415v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Mallat, Z. Articles by Tedgui, A. Search for Related Content PubMed PubMed Citation Articles by Mallat, Z. Articles by Tedgui, A. Related Collections Pathophysiology Mechanism of atherosclerosis/growth factors

(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.

	References

Top Abstract Introduction Materials and Methods Results Discussion References

 
1. Ross R. Atherosclerosis: an inflammatory disease. N Engl J Med. 1999; 340: 115–126.

2. Lee RT, Libby P. The unstable atheroma. Arterioscler Thromb Vasc Biol. 1997; 17: 1859–1867.

3. Uyemura K, Demer LL, Castle SC, Jullien D, Berliner JA, Gately MK, Warrier RR, Pham N, Fogelman AM, Modlin RL. Cross-regulatory roles of interleukin (IL)-12 and IL-10 in atherosclerosis. J Clin Invest. 1996; 97: 2130–138.

4. Mallat Z, Heymes C, Ohan J, Faggin E, Lesèche G, Tedgui A. Expression of interleukin-10 in advanced human atherosclerotic plaques: relation to inducible nitric oxide synthase expression and cell death. Arterioscler Thromb Vasc Biol. 1999; 19: 611–616.

5. Pinderski Oslund LJ, Hedrick CC, Olvera T, Hagenbaugh A, Territo M, Berliner JA, Fyfe AI. Interleukin-10 blocks atherosclerotic events in vitro and in vivo. Arterioscler Thromb Vasc Biol. 1999; 19: 2847–2853.

6. Mallat Z, Besnard S, Duriez M, Deleuze V, Emmanuel F, Bureau MF, Soubrier F, Esposito B, Duez H, Fievet C, Staels B, Duverger N, Scherman D, Tedgui A. Protective role of interleukin-10 in atherosclerosis. Circ Res. 1999; 85: e17–e24.

7. George J, Shoenfeld Y, Gilburd B, Afek A, Shaish A, Harats D. Requisite role for interleukin-4 in the acceleration of fatty streaks induced by heat shock protein 65 or Mycobacterium tuberculosis. Circ Res. 2000; 86: 1203–1210.

8. Bobik A, Agrotis A, Kanellakis P, Dilley R, Krushinsky A, Smirnov V, Tararak E, Condron M, Kostolias G. Distinct patterns of transforming growth factor-ß isoform and receptor expression in human atherosclerotic lesions: colocalization implicates TGF-ß in fibrofatty lesion development. Circulation. 1999; 99: 2883–2891.

9. Lutgens E, Cleutjens KB, Heeneman S, Koteliansky VE, Burkly LC, Daemen MJ. Both early and delayed anti-CD40L antibody treatment induces a stable plaque phenotype. Proc Natl Acad Sci U S A. 2000; 97: 7464–7469.

10. Vodovotz Y, Bogdan C, Paik J, Xie QW, Nathan C. Mechanisms of suppression of macrophage nitric oxide release by transforming growth factor-ß. J Exp Med. 1993; 178: 605–613.

11. Grainger DJ, Mosedale DE, Metcalfe JC, Bottinger EP. Dietary fat and reduced levels of TGFß1 act synergistically to promote activation of the vascular endothelium and formation of lipid lesions. J Cell Sci. 2000; 113: 2355–2361.

12. Grainger DJ, Metcalfe JC. Pivotal role for TGF-ß in atherogenesis? Biol Rev Camb Philos Soc. 1995; 70: 571–596.

13. Blann AD, Wang JM, Wilson PB, Kumar S. Serum levels of the TGF-ß receptor are increased in atherosclerosis. Atherosclerosis. 1996; 120: 221–226.

14. Erren M, Reinecke H, Junker R, Fobker M, Schulte H, Schurek JO, Kropf J, Kerber S, Breithardt G, Assmann G, Cullen P. Systemic inflammatory parameters in patients with atherosclerosis of the coronary and peripheral arteries. Arterioscler Thromb Vasc Biol. 1999; 19: 2355–2363.

15. Yokota M, Ichihara S, Lin TL, Nakashima N, Yamada Y. Association of a T29C polymorphism of the transforming growth factor-ß1 gene with genetic susceptibility to myocardial infarction in Japanese. Circulation. 2000; 101: 2783–2787.

16. Wang XL, Liu SX, Wilcken DEL. Circulating transforming growth factor ß1 and coronary artery disease. Cardiovasc Res. 1997; 34: 404–410.

17. McCaffrey TA, Du B, Consigli S, Szabo P, Bray PJ, Hartner L, Weksler BB, Sanborn TA, Bergman G, Bush HLJr. Genomic instability in the type II TGF-ß1 receptor gene in atherosclerotic and restenotic vascular cells. J Clin Invest. 1997; 100: 2182–2188.

18. McCaffrey TA. TGF-ßs and TGF-ß receptors in atherosclerosis. Cytokine Growth Factor Rev. 2000; 11: 103–114.

19. Lucas C, Bald LN, Fendly BM, Mora-Worms M, Figari IS, Patzer EJ, Palladino MA. The autocrine production of transforming growth factor-ß1 during lymphocyte activation: a study with a monoclonal antibody-based ELISA. J Immunol. 1990; 145: 1415–1422.

20. Arteaga CL, Hurd SD, Winnier AR, Johnson MD, Fendly BM, Forbes JT. Anti-transforming growth factor (TGF)-ß antibodies inhibit breast cancer cell tumorigenicity and increase mouse spleen natural killer cell activity: implications for a possible role of tumor cell/host TGF-ß interactions in human breast cancer progression. J Clin Invest. 1993; 92: 2569–2576.

21. Randall LA, Wadhwa M, Thorpe R, Mire-Sluis AR. A novel, sensitive bioassay for transforming growth factor-ß. J Immunol Methods. 1993; 164: 61–67.

22. Kulkarni AB, Ward JM, Yaswen L, Mackall CL, Bauer SR, Huh CG, Gress RE, Karlsson S. Transforming growth factor-ß1 knockout mice: a animal model for inflammatory disorders. Am J Pathol. 1995; 146: 264–275.

23. Shull MM, Ormsby I, Kier AB, Pawlowski S, Diebold RJ, Yin M, Allen R, Sidman C, Proetzel G, Calvin D, et al. Targeted disruption of the mouse transforming growth factor-ß1 gene results in multifocal inflammatory disease. Nature. 1992; 359: 693–699.

24. Border WA, Noble NA. Transforming growth factor ß in tissue fibrosis. N Engl J Med. 1994; 331: 1286–1292.

25. Pollman MJ, Naumovski L, Gibbons GH. Vascular cell apoptosis: cell type-specific modulation by transforming growth factor-ß1 in endothelial cells versus smooth muscle cells. Circulation. 1999; 99: 2019–2026.

26. Topper JN. TGF-ß in the cardiovascular system: molecular mechanisms of a context-specific growth factor. Trends Cardiovasc Med. 2000; 10: 132–137.

27. DiChiara MR, Kiely JM, Gimbrone MA, Lee ME, Perrella MA, Topper JN. Inhibition of E-selectin gene expression by transforming growth factor ß in endothelial cells involves coactivator integration of Smad and nuclear factor-B–mediated signals. J Exp Med. 2000; 192: 695–704.

28. Park SK, Yang WS, Lee SK, Ahn H, Park JS, Hwang O, Lee JD. TGF-ß₁ down-regulates inflammatory cytokine-induced VCAM-1 expression in cultured human glomerular endothelial cells. Nephrol Dial Transplant. 2000; 15: 596–604.

29. Gamble JR, Bradley S, Noack L, Vadas MA. TGF-ß and endothelial cells inhibit VCAM-1 expression on human vascular smooth muscle cells. Arterioscler Thromb Vasc Biol. 1995; 15: 949–955.

30. Weiss JM, Cuff CA, Berman JW. TGF-ß downmodulates cytokine-induced monocyte chemoattractant protein (MCP)-1 expression in human endothelial cells: a putative role for TGF-ß in the modulation of TNF receptor expression. Endothelium. 1999; 6: 291–302.

31. Smith WB, Noack L, Khew-Goodall Y, Isenmann S, Vadas MA, Gamble JR. Transforming growth factor-ß1 inhibits the production of IL-8 and the transmigration of neutrophils through activated endothelium. J Immunol. 1996; 157: 360–368.

32. Grainger DJ, Kemp PR, Liu AC, Lawn RM, Metcalfe JC. Activation of transforming growth factor-ß is inhibited in transgenic apolipoprotein(a) mice. Nature. 1994; 370: 460–462.

33. Grainger DJ, Kemp BR, Metcalfe JC, Liu AC, Lawn RM, Williams NR, Grace AA, Schofield PM, Chauhan A. The serum concentration of active transforming growth factor-ß is severely depressed in advanced atherosclerosis. Nat Med. 1995; 1: 74–79.

34. Grainger DJ, Witchell CM, Metcalfe JC. Tamoxifen elevates transforming growth factor-ß and suppresses diet-induced formation of lipid lesions in mouse aorta. Nat Med. 1995; 1: 1067–1073.

This article has been cited by other articles:

				H. J. Kim, M. Y. Kim, H. Jin, H. J. Kim, S. S. Kang, H. J. Kim, J. H. Lee, K. C. Chang, J.-Y. Hwang, C. Yabe-Nishimura, et al. Peroxisome Proliferator-Activated Receptor {delta} Regulates Extracellular Matrix and Apoptosis of Vascular Smooth Muscle Cells Through the Activation of Transforming Growth Factor-{beta}1/Smad3 Circ. Res., July 2, 2009; 105(1): 16 - 24. [Abstract] [Full Text] [PDF]

				Z. Chen and E. Tzima PECAM-1 Is Necessary for Flow-Induced Vascular Remodeling Arterioscler. Thromb. Vasc. Biol., July 1, 2009; 29(7): 1067 - 1073. [Abstract] [Full Text] [PDF]

				T. Chen, Z. Huang, L. Wang, Y. Wang, F. Wu, S. Meng, and C. Wang MicroRNA-125a-5p partly regulates the inflammatory response, lipid uptake, and ORP9 expression in oxLDL-stimulated monocyte/macrophages Cardiovasc Res, July 1, 2009; 83(1): 131 - 139. [Abstract] [Full Text] [PDF]

				Z. Mallat, S. Taleb, H. Ait-Oufella, and A. Tedgui The role of adaptive T cell immunity in atherosclerosis J. Lipid Res., April 1, 2009; 50(Supplement): S364 - S369. [Abstract] [Full Text] [PDF]

				C. E. Toutain, L. Brouchet, I. Raymond-Letron, P. Vicendo, H. Berges, J. Favre, M.-J. Fouque, A. Krust, A.-M. Schmitt, P. Chambon, et al. Prevention of Skin Flap Necrosis by Estradiol Involves Reperfusion of a Protected Vascular Network Circ. Res., January 30, 2009; 104(2): 245 - 254. [Abstract] [Full Text] [PDF]

				K. Furuichi, J.-L. Gao, R. Horuk, T. Wada, S. Kaneko, and P. M. Murphy Chemokine Receptor CCR1 Regulates Inflammatory Cell Infiltration after Renal Ischemia-Reperfusion Injury J. Immunol., December 15, 2008; 181(12): 8670 - 8676. [Abstract] [Full Text] [PDF]

				D. Sheppard The role of integrins in pulmonary fibrosis Eur. Respir. Rev., December 1, 2008; 17(109): 157 - 162. [Abstract] [Full Text] [PDF]

				P. G. Wilson, J. C. Thompson, N. R. Webb, F. C. de Beer, V. L. King, and L. R. Tannock Serum Amyloid A, but Not C-Reactive Protein, Stimulates Vascular Proteoglycan Synthesis in a Pro-Atherogenic Manner Am. J. Pathol., December 1, 2008; 173(6): 1902 - 1910. [Abstract] [Full Text] [PDF]

				I. Gotsman, A. H. Sharpe, and A. H. Lichtman T-Cell Costimulation and Coinhibition in Atherosclerosis Circ. Res., November 21, 2008; 103(11): 1220 - 1231. [Abstract] [Full Text] [PDF]

				R. Moura, M. Tjwa, P. Vandervoort, S. Van kerckhoven, P. Holvoet, and M. F. Hoylaerts Thrombospondin-1 Deficiency Accelerates Atherosclerotic Plaque Maturation in ApoE-/- Mice Circ. Res., November 7, 2008; 103(10): 1181 - 1189. [Abstract] [Full Text] [PDF]

				S. Belmadani, M. Zerfaoui, H. A. Boulares, D. I. Palen, and K. Matrougui Microvessel vascular smooth muscle cells contribute to collagen type I deposition through ERK1/2 MAP kinase, {alpha}v{beta}3-integrin, and TGF-{beta}1 in response to ANG II and high glucose Am J Physiol Heart Circ Physiol, July 1, 2008; 295(1): H69 - H76. [Abstract] [Full Text] [PDF]

				C. Rodriguez, J. Martinez-Gonzalez, B. Raposo, J. F. Alcudia, A. Guadall, and L. Badimon Regulation of lysyl oxidase in vascular cells: lysyl oxidase as a new player in cardiovascular diseases Cardiovasc Res, July 1, 2008; 79(1): 7 - 13. [Abstract] [Full Text] [PDF]

				A. C. Doran, N. Meller, and C. A. McNamara Role of Smooth Muscle Cells in the Initiation and Early Progression of Atherosclerosis Arterioscler. Thromb. Vasc. Biol., May 1, 2008; 28(5): 812 - 819. [Abstract] [Full Text] [PDF]

				F. Huang, J. C. Thompson, P. G. Wilson, H. H. Aung, J. C. Rutledge, and L. R. Tannock Angiotensin II increases vascular proteoglycan content preceding and contributing to atherosclerosis development J. Lipid Res., March 1, 2008; 49(3): 521 - 530. [Abstract] [Full Text] [PDF]

				D. Bishop-Bailey Peroxisome Proliferator-Activated Receptor {beta}/{delta} Goes Vascular Circ. Res., February 1, 2008; 102(2): 146 - 147. [Full Text] [PDF]

				H. J. Kim, S. A. Ham, S. U. Kim, J.-Y. Hwang, J.-H. Kim, K. C. Chang, C. Yabe-Nishimura, J.-H. Kim, and H. G. Seo Transforming Growth Factor-{beta}1 Is a Molecular Target for the Peroxisome Proliferator-Activated Receptor {delta} Circ. Res., February 1, 2008; 102(2): 193 - 200. [Abstract] [Full Text] [PDF]

				O. Phan, O. Ivanovski, I. G. Nikolov, N. Joki, J. Maizel, L. Louvet, M. Chasseraud, T. Nguyen-Khoa, B. Lacour, T. B. Drueke, et al. Effect of oral calcium carbonate on aortic calcification in apolipoprotein E-deficient (apoE-/-) mice with chronic renal failure Nephrol. Dial. Transplant., January 1, 2008; 23(1): 82 - 90. [Abstract] [Full Text] [PDF]

				T. Korff, K. Aufgebauer, and M. Hecker Cyclic Stretch Controls the Expression of CD40 in Endothelial Cells by Changing Their Transforming Growth Factor-{beta}1 Response Circulation, November 13, 2007; 116(20): 2288 - 2297. [Abstract] [Full Text] [PDF]

				H.R.S. Girn, N.M. Orsi, and S. Homer-Vanniasinkam An overview of cytokine interactions in atherosclerosis and implications for peripheral arterial disease Vascular Medicine, November 1, 2007; 12(4): 299 - 309. [Abstract] [PDF]

				C.-L. Chen, I-H. Liu, S. J. Fliesler, X. Han, S. S. Huang, and J. S. Huang Cholesterol suppresses cellular TGF-beta responsiveness: implications in atherogenesis J. Cell Sci., October 15, 2007; 120(20): 3509 - 3521. [Abstract] [Full Text] [PDF]

				P. Gourdy, A. Schambourg, C. Filipe, V. Douin-Echinard, B. Garmy-Susini, B. Calippe, F. Terce, F. Bayard, and J.-F. Arnal Transforming Growth Factor Activity Is a Key Determinant for the Effect of Estradiol on Fatty Streak Deposit in Hypercholesterolemic Mice Arterioscler. Thromb. Vasc. Biol., October 1, 2007; 27(10): 2214 - 2221. [Abstract] [Full Text] [PDF]

				E. Suganuma, V. R. Babaev, M. Motojima, Y. Zuo, N. Ayabe, A. B. Fogo, I. Ichikawa, M. F. Linton, S. Fazio, and V. Kon Angiotensin Inhibition Decreases Progression of Advanced Atherosclerosis and Stabilizes Established Atherosclerotic Plaques J. Am. Soc. Nephrol., August 1, 2007; 18(8): 2311 - 2319. [Abstract] [Full Text] [PDF]

				J. L. Mehta and H. Attramadal The TGF{beta} superfamily in cardiovascular biology Cardiovasc Res, May 1, 2007; 74(2): 181 - 183. [Full Text] [PDF]

				D. J. Grainger TGF-{beta} and atherosclerosis in man Cardiovasc Res, May 1, 2007; 74(2): 213 - 222. [Abstract] [Full Text] [PDF]

				P. L. Hermonat, D. Li, B. Yang, and J. L. Mehta Mechanism of action and delivery possibilities for TGF{beta}1 in the treatment of myocardial ischemia Cardiovasc Res, May 1, 2007; 74(2): 235 - 243. [Abstract] [Full Text] [PDF]

				A.-K. L. Robertson and G. K Hansson T Cells in Atherogenesis: For Better or For Worse? Arterioscler. Thromb. Vasc. Biol., November 1, 2006; 26(11): 2421 - 2432. [Abstract] [Full Text] [PDF]

				S. Steffens, F. Burger, G. Pelli, Y. Dean, G. Elson, M. Kosco-Vilbois, L. Chatenoud, and F. Mach Short-Term Treatment With Anti-CD3 Antibody Reduces the Development and Progression of Atherosclerosis in Mice Circulation, October 31, 2006; 114(18): 1977 - 1984. [Abstract] [Full Text] [PDF]

				K. Furuichi, J.-L. Gao, and P. M. Murphy Chemokine Receptor CX3CR1 Regulates Renal Interstitial Fibrosis after Ischemia-Reperfusion Injury Am. J. Pathol., August 1, 2006; 169(2): 372 - 387. [Abstract] [Full Text] [PDF]

				A. Bobik Transforming Growth Factor-{beta}s and Vascular Disorders Arterioscler. Thromb. Vasc. Biol., August 1, 2006; 26(8): 1712 - 1720. [Abstract] [Full Text] [PDF]

				N. N. Singh and D. P. Ramji Transforming Growth Factor-{beta}-Induced Expression of the Apolipoprotein E Gene Requires c-Jun N-Terminal Kinase, p38 Kinase, and Casein Kinase 2 Arterioscler. Thromb. Vasc. Biol., June 1, 2006; 26(6): 1323 - 1329. [Abstract] [Full Text] [PDF]

				W. Koch, P. Hoppmann, J. C. Mueller, A. Schomig, and A. Kastrati Association of Transforming Growth Factor-{beta}1 Gene Polymorphisms With Myocardial Infarction in Patients With Angiographically Proven Coronary Heart Disease Arterioscler. Thromb. Vasc. Biol., May 1, 2006; 26(5): 1114 - 1119. [Abstract] [Full Text] [PDF]

				A. Tedgui and Z. Mallat Cytokines in Atherosclerosis: Pathogenic and Regulatory Pathways Physiol Rev, April 1, 2006; 86(2): 515 - 581. [Abstract] [Full Text] [PDF]

				Y. Li, M.-C. Gerbod-Giannone, H. Seitz, D. Cui, E. Thorp, A. R. Tall, G. K. Matsushima, and I. Tabas Cholesterol-induced Apoptotic Macrophages Elicit an Inflammatory Response in Phagocytes, Which Is Partially Attenuated by the Mer Receptor J. Biol. Chem., March 10, 2006; 281(10): 6707 - 6717. [Abstract] [Full Text] [PDF]

				S. P. Tull, S. I. Anderson, S. C. Hughan, S. P. Watson, G. B. Nash, and G. E. Rainger Cellular Pathology of Atherosclerosis: Smooth Muscle Cells Promote Adhesion of Platelets to Cocultured Endothelial Cells Circ. Res., January 6, 2006; 98(1): 98 - 104. [Abstract] [Full Text] [PDF]

				R. Kraemer, P. J. Baker, K. C. Kent, Y. Ye, J. J. Han, R. Tejada, M. Silane, R. Upmacis, R. Deeb, Y. Chen, et al. Decreased Neurotrophin TrkB Receptor Expression Reduces Lesion Size in the Apolipoprotein E-Null Mutant Mouse Circulation, December 6, 2005; 112(23): 3644 - 3653. [Abstract] [Full Text] [PDF]

				U. Seay, D. Sedding, S. Krick, M. Hecker, W. Seeger, and O. Eickelberg Transforming Growth Factor-{beta}-Dependent Growth Inhibition in Primary Vascular Smooth Muscle Cells Is p38-Dependent J. Pharmacol. Exp. Ther., December 1, 2005; 315(3): 1005 - 1012. [Abstract] [Full Text] [PDF]

				V. L. Sales, G. K. Sukhova, M. A. Lopez-Ilasaca, P. Libby, V. J. Dzau, and R. E. Pratt Angiotensin Type 2 Receptor Is Expressed in Murine Atherosclerotic Lesions and Modulates Lesion Evolution Circulation, November 22, 2005; 112(21): 3328 - 3336. [Abstract] [Full Text] [PDF]

				M. W. Feinberg, Z. Cao, A. K. Wara, M. A. Lebedeva, S. SenBanerjee, and M. K. Jain Kruppel-like Factor 4 Is a Mediator of Proinflammatory Signaling in Macrophages J. Biol. Chem., November 18, 2005; 280(46): 38247 - 38258. [Abstract] [Full Text] [PDF]

				D. J. Grainger and P. M. Schofield Tamoxifen for the Prevention of Myocardial Infarction in Humans: Preclinical and Early Clinical Evidence Circulation, November 8, 2005; 112(19): 3018 - 3024. [Full Text] [PDF]

				E. Fosslien Cardiovascular Complications of Non-Steroidal Anti-Inflammatory Drugs Ann. Clin. Lab. Sci., October 1, 2005; 35(4): 347 - 385. [Abstract] [Full Text] [PDF]

				J. P.G. Sluijter, R. E. Verloop, W. P.C. Pulskens, E. Velema, J. M. Grimbergen, P. H. Quax, M.-J. Goumans, G. Pasterkamp, and D. P.V. de Kleijn Involvement of furin-like proprotein convertases in the arterial response to injury Cardiovasc Res, October 1, 2005; 68(1): 136 - 143. [Abstract] [Full Text] [PDF]

				J. Dai, F. Losy, A.-M. Guinault, C. Pages, I. Anegon, P. Desgranges, J.-P. Becquemin, and E. Allaire Overexpression of Transforming Growth Factor-{beta}1 Stabilizes Already-Formed Aortic Aneurysms: A First Approach to Induction of Functional Healing by Endovascular Gene Therapy Circulation, August 16, 2005; 112(7): 1008 - 1015. [Abstract] [Full Text] [PDF]

				G. Caligiuri, E. Groyer, J. Khallou-Laschet, A. A. H. Zen, J. Sainz, D. Urbain, A.-T. Gaston, M. Lemitre, A. Nicoletti, and A. Lafont Reduced Immunoregulatory CD31+ T Cells in the Blood of Atherosclerotic Mice With Plaque Thrombosis Arterioscler. Thromb. Vasc. Biol., August 1, 2005; 25(8): 1659 - 1664. [Abstract] [Full Text] [PDF]

				E. W. Raines and N. Ferri Thematic Review Series: The Immune System and Atherogenesis. Cytokines affecting endothelial and smooth muscle cells in vascular disease J. Lipid Res., June 1, 2005; 46(6): 1081 - 1092. [Abstract] [Full Text] [PDF]

				G. D. Norata, E. Callegari, M. Marchesi, G. Chiesa, P. Eriksson, and A. L. Catapano High-Density Lipoproteins Induce Transforming Growth Factor-{beta}2 Expression in Endothelial Cells Circulation, May 31, 2005; 111(21): 2805 - 2811. [Abstract] [Full Text] [PDF]

				H. Okada, G. Takemura, K.-i. Kosai, Y. Li, T. Takahashi, M. Esaki, K. Yuge, S. Miyata, R. Maruyama, A. Mikami, et al. Postinfarction Gene Therapy Against Transforming Growth Factor-{beta} Signal Modulates Infarct Tissue Dynamics and Attenuates Left Ventricular Remodeling and Heart Failure Circulation, May 17, 2005; 111(19): 2430 - 2437. [Abstract] [Full Text] [PDF]

				M. P.J. de Winther, E. Kanters, G. Kraal, and M. H. Hofker Nuclear Factor {kappa}B Signaling in Atherogenesis Arterioscler. Thromb. Vasc. Biol., May 1, 2005; 25(5): 904 - 914. [Abstract] [Full Text] [PDF]

				K. Kobayashi, K. Yokote, M. Fujimoto, K. Yamashita, A. Sakamoto, M. Kitahara, H. Kawamura, Y. Maezawa, S. Asaumi, T. Tokuhisa, et al. Targeted Disruption of TGF-{beta}-Smad3 Signaling Leads to Enhanced Neointimal Hyperplasia With Diminished Matrix Deposition in Response to Vascular Injury Circ. Res., April 29, 2005; 96(8): 904 - 912. [Abstract] [Full Text] [PDF]

				S. A. Irvine, P. Foka, S. A. Rogers, J. R. Mead, and D. P. Ramji A critical role for the Sp1-binding sites in the transforming growth factor-{beta}-mediated inhibition of lipoprotein lipase gene expression in macrophages Nucleic Acids Res., March 8, 2005; 33(5): 1423 - 1434. [Abstract] [Full Text] [PDF]

				Y. Naiki, K. S. Michelsen, W. Zhang, S. Chen, T. M. Doherty, and M. Arditi Transforming Growth Factor-{beta} Differentially Inhibits MyD88-dependent, but Not TRAM- and TRIF-dependent, Lipopolysaccharide-induced TLR4 Signaling J. Biol. Chem., February 18, 2005; 280(7): 5491 - 5495. [Abstract] [Full Text] [PDF]

				A. Tedgui The role of inflammation in atherothrombosis: implications for clinical practice Vascular Medicine, February 1, 2005; 10(1): 45 - 53. [Abstract] [PDF]

				Z. A. Massy, O. Ivanovski, T. Nguyen-Khoa, J. Angulo, D. Szumilak, N. Mothu, O. Phan, M. Daudon, B. Lacour, T. B. Drueke, et al. Uremia Accelerates both Atherosclerosis and Arterial Calcification in Apolipoprotein E Knockout Mice J. Am. Soc. Nephrol., January 1, 2005; 16(1): 109 - 116. [Abstract] [Full Text] [PDF]

				F. Cipollone, M. Fazia, G. Mincione, A. Iezzi, B. Pini, C. Cuccurullo, S. Ucchino, F. Spigonardo, M. Di Nisio, F. Cuccurullo, et al. Increased Expression of Transforming Growth Factor-{beta}1 as a Stabilizing Factor in Human Atherosclerotic Plaques Stroke, October 1, 2004; 35(10): 2253 - 2257. [Abstract] [Full Text] [PDF]

				Y. Nakai, K. Iwabuchi, S. Fujii, N. Ishimori, N. Dashtsoodol, K. Watano, T. Mishima, C. Iwabuchi, S. Tanaka, J. S. Bezbradica, et al. Natural killer T cells accelerate atherogenesis in mice Blood, October 1, 2004; 104(7): 2051 - 2059. [Abstract] [Full Text] [PDF]

				N. Kalinina, A. Agrotis, Y. Antropova, O. Ilyinskaya, V. Smirnov, E. Tararak, and A. Bobik Smad Expression in Human Atherosclerotic Lesions: Evidence for Impaired TGF-{beta}/Smad Signaling in Smooth Muscle Cells of Fibrofatty Lesions Arterioscler. Thromb. Vasc. Biol., August 1, 2004; 24(8): 1391 - 1396. [Abstract] [Full Text] [PDF]

				G. K. Owens, M. S. Kumar, and B. R. Wamhoff Molecular Regulation of Vascular Smooth Muscle Cell Differentiation in Development and Disease Physiol Rev, July 1, 2004; 84(3): 767 - 801. [Abstract] [Full Text] [PDF]

				G. K. Hansson, A.-K. L. Robertson, and D. J. Grainger TGF-{beta} in Atherosclerosis Arterioscler. Thromb. Vasc. Biol., June 1, 2004; 24(6): e137 - e138. [Full Text] [PDF]

				M. W. Feinberg, M. Watanabe, M. A. Lebedeva, A. S. Depina, J.-i. Hanai, T. Mammoto, J. P. Frederick, X.-F. Wang, V. P. Sukhatme, and M. K. Jain Transforming Growth Factor-{beta}1 Inhibition of Vascular Smooth Muscle Cell Activation Is Mediated via Smad3 J. Biol. Chem., April 16, 2004; 279(16): 16388 - 16393. [Abstract] [Full Text] [PDF]

				M. W. Feinberg, K. Shimizu, M. Lebedeva, R. Haspel, K. Takayama, Z. Chen, J. P. Frederick, X.-F. Wang, D. I. Simon, P. Libby, et al. Essential Role for Smad3 in Regulating MCP-1 Expression and Vascular Inflammation Circ. Res., March 19, 2004; 94(5): 601 - 608. [Abstract] [Full Text] [PDF]

				D. J. Grainger Transforming Growth Factor {beta} and Atherosclerosis: So Far, So Good for the Protective Cytokine Hypothesis Arterioscler. Thromb. Vasc. Biol., March 1, 2004; 24(3): 399 - 404. [Abstract] [Full Text]

				E. Lutgens, R.-J. van Suylen, B. C. Faber, M. J. Gijbels, P. M. Eurlings, A.-P. Bijnens, K. B. Cleutjens, S. Heeneman, and M. J.A.P. Daemen Atherosclerotic Plaque Rupture: Local or Systemic Process? Arterioscler. Thromb. Vasc. Biol., December 1, 2003; 23(12): 2123 - 2130. [Abstract] [Full Text] [PDF]

				A. Gojova, V. Brun, B. Esposito, F. Cottrez, P. Gourdy, P. Ardouin, A. Tedgui, Z. Mallat, and H. Groux Specific abrogation of transforming growth factor-{beta} signaling in T cells alters atherosclerotic lesion size and composition in mice Blood, December 1, 2003; 102(12): 4052 - 4058. [Abstract] [Full Text] [PDF]

				Y. Liu, S. Sinha, and G. Owens A Transforming Growth Factor-{beta} Control Element Required for SM {alpha}-Actin Expression in Vivo Also Partially Mediates GKLF-dependent Transcriptional Repression J. Biol. Chem., November 28, 2003; 278(48): 48004 - 48011. [Abstract] [Full Text] [PDF]

				J. H. Von der Thusen, J. Kuiper, T. J. C. Van Berkel, and E. A. L. Biessen Interleukins in Atherosclerosis: Molecular Pathways and Therapeutic Potential Pharmacol. Rev., March 1, 2003; 55(1): 133 - 166. [Abstract] [Full Text] [PDF]

				E. Lutgens, M. Gijbels, M. Smook, P. Heeringa, P. Gotwals, V. E. Koteliansky, and M. J.A.P. Daemen Transforming Growth Factor-{beta} Mediates Balance Between Inflammation and Fibrosis During Plaque Progression Arterioscler. Thromb. Vasc. Biol., June 1, 2002; 22(6): 975 - 982. [Abstract] [Full Text] [PDF]

				H. Williams, J. L. Johnson, K. G. S. Carson, and C. L. Jackson Characteristics of Intact and Ruptured Atherosclerotic Plaques in Brachiocephalic Arteries of Apolipoprotein E Knockout Mice Arterioscler. Thromb. Vasc. Biol., May 1, 2002; 22(5): 788 - 792. [Abstract] [Full Text] [PDF]

				E. Lutgens and M. J.A.P. Daemen Transforming Growth Factor-{beta}: A Local or Systemic Mediator of Plaque Stability? Circ. Res., November 9, 2001; 89(10): 853 - 855. [Full Text] [PDF]

This Article Abstract Full Text (PDF) All Versions of this Article: 89/10/930    most recent hh2201.099415v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Mallat, Z. Articles by Tedgui, A. Search for Related Content PubMed PubMed Citation Articles by Mallat, Z. Articles by Tedgui, A. Related Collections Pathophysiology Mechanism of atherosclerosis/growth factors