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• W36424441 abstract "Animal models are designed to be preliminary tools for better understanding of the pathogenesis, improvement in diagnosis, prevention, and therapy of arteriosclerosis in humans. Attracted by the well-defined genetic systems, a number of investigators have begun to use the mouse as an experimental system for arteriosclerosis research. Hundreds of inbred lines have been established, and the genetic map is relatively well defined, and both congenic strains and recombinant strains are available to facilitate genetic experimentation. Because arteriosclerosis is a complicated disease, which includes spontaneous (native) atherosclerosis, transplant arteriosclerosis, vein graft atherosclerosis, and angioplasty-induced restenosis, several mouse models for studying all types of arteriosclerosis have recently been established. Using these mouse models, much knowledge concerning the pathogenesis of the disease and therapeutic intervention has been gained, eg, origins of endothelial and smooth muscle cells in lesions of transplant and vein graft atherosclerosis. This review will not attempt to cover all aspects of mouse models, rather focus on models of arterial injuries, vein grafts, and transplant arteriosclerosis, by which the major progress in understanding the mechanisms of the disease has been made. This article will also point out (dis)advantages of a variety of models, and how the models can be appropriately chosen for different purposes of study. Animal models are designed to be preliminary tools for better understanding of the pathogenesis, improvement in diagnosis, prevention, and therapy of arteriosclerosis in humans. Attracted by the well-defined genetic systems, a number of investigators have begun to use the mouse as an experimental system for arteriosclerosis research. Hundreds of inbred lines have been established, and the genetic map is relatively well defined, and both congenic strains and recombinant strains are available to facilitate genetic experimentation. Because arteriosclerosis is a complicated disease, which includes spontaneous (native) atherosclerosis, transplant arteriosclerosis, vein graft atherosclerosis, and angioplasty-induced restenosis, several mouse models for studying all types of arteriosclerosis have recently been established. Using these mouse models, much knowledge concerning the pathogenesis of the disease and therapeutic intervention has been gained, eg, origins of endothelial and smooth muscle cells in lesions of transplant and vein graft atherosclerosis. This review will not attempt to cover all aspects of mouse models, rather focus on models of arterial injuries, vein grafts, and transplant arteriosclerosis, by which the major progress in understanding the mechanisms of the disease has been made. This article will also point out (dis)advantages of a variety of models, and how the models can be appropriately chosen for different purposes of study. Arteriosclerosis is characterized by smooth muscle cell hyperplasia or hypertrophy and matrix protein accumulation in the intima and/or media with or without lipid deposition, resulting in thickening and stiffness of the arterial wall.1Stary HC Chandler AB Glagov S Guyton JR Insull Jr, W Rosenfeld ME Schaffer SA Schwartz CJ Wagner WD Wissler RW A definition of initial, fatty streak, and intermediate lesions of atherosclerosis. A report from the Committee on Vascular Lesions of the Council on Arteriosclerosis, American Heart Association.Circulation. 1994; 89: 2462-2478Crossref PubMed Scopus (992) Google Scholar Arteriosclerosis includes (spontaneous) atherosclerosis, accelerated arteriosclerosis (namely, transplant arteriosclerosis), restenosis after percutaneous transluminal coronary angioplasty, and vein graft atherosclerosis.2Ip JH Fuster V Badimon L Badimon J Taubman MB Chesebro JH Syndromes of accelerated atherosclerosis: role of vascular injury and smooth muscle cell proliferation.J Am Coll Cardiol. 1990; 15: 1667-1687Abstract Full Text PDF PubMed Scopus (697) Google Scholar Atherosclerosis research with animal models, as known today, is nearly 100 years old.3Ignatowski AC Influence of animal food on the organism of rabbits.Izvest Imper Voennomed Akad St Petersburg. 1908; 16: 154-173Google Scholar Knowledge of the pathogenesis and therapy of atherosclerotic disease and the use of animal models in arteriosclerosis research have evolved almost simultaneously. The use of animal models in the study of arteriosclerosis is essential to answer many questions. For instance, evaluation of a risk factor as a single independent variable, with almost complete exclusion of other factors, can best be performed in animals free of intercurrent diseases or abnormalities and with well known genetic characteristics.4Breslow JL Transgenic mouse models of lipoprotein metabolism and atherosclerosis.Proc Natl Acad Sci USA. 1993; 90: 8314-8318Crossref PubMed Scopus (112) Google Scholar On the other hand, the role of vascular injury because of angioplasty, alloimmune responses, or vein grafts can be investigated alone or in combination with other factors that either aggravate or have beneficial effects. Furthermore, experiments using animals are the only way to develop and test new diagnostic, preventive, and therapeutic procedures for both ethical and practical reasons. The investigator can choose the species, time, and method, as well as obtain tissue, and serum samples as well as other material needed for measurements under optimal conditions, selective circumstances that are difficult, if not impossible, in studies with human patients.Attracted by the availability of well-defined genetic systems of transgenic and knockout mice, a number of investigators have begun to use the mouse as an experimental system for arteriosclerosis research.4Breslow JL Transgenic mouse models of lipoprotein metabolism and atherosclerosis.Proc Natl Acad Sci USA. 1993; 90: 8314-8318Crossref PubMed Scopus (112) Google Scholar Hundreds of inbred lines have been established, and the genetic map is relatively well defined, and both congenic strains and recombinant strains are available to facilitate genetic experimentation. The animal model of hyperlipidemia and atherosclerosis in apoE- and low-density lipoprotein receptor-deficient mice has been widely used.4Breslow JL Transgenic mouse models of lipoprotein metabolism and atherosclerosis.Proc Natl Acad Sci USA. 1993; 90: 8314-8318Crossref PubMed Scopus (112) Google Scholar, 5Knowles JW Maeda N Genetic modifiers of atherosclerosis in mice.Arterioscler Thromb Vasc Biol. 2000; 20: 2336-2345Crossref PubMed Scopus (125) Google Scholar, 6de Winther MP Hofker MH New mouse models for lipoprotein metabolism and atherosclerosis.Curr Opin Lipidol. 2002; 13: 191-197Crossref PubMed Scopus (18) Google Scholar Such mouse models have considerable advantages over other animal systems in that they overcome the need to administer a cholesterol diet. Since several reviews summarizing the effects of a variety of genes on native atherosclerosis have been published,5Knowles JW Maeda N Genetic modifiers of atherosclerosis in mice.Arterioscler Thromb Vasc Biol. 2000; 20: 2336-2345Crossref PubMed Scopus (125) Google Scholar, 7Allayee H Ghazalpour A Lusis AJ Using mice to dissect genetic factors in atherosclerosis.Arterioscler Thromb Vasc Biol. 2003; 23: 1501-1509Crossref PubMed Scopus (45) Google Scholar the present subtitle will not cover the animal models of spontaneous atherosclerosis, ie, hyperlipidemia-induced atherosclerosis, rather focus on other types of mouse models for arteriosclerosis, including arterial injuries, vein graft, and vessel transplantation.Arterial InjuriesAngioplasty is very often used to treat patients with severe coronary artery disease. The coronary blood flow in the majority of patients is recovered after the treatment. The problem is restenosis of the vessel because of the formation of neointimal lesions.8Levine GN Chodos AP Loscalzo J Restenosis following coronary angioplasty: clinical presentations and therapeutic options.Clin Cardiol. 1995; 18: 693-703Crossref PubMed Scopus (51) Google Scholar The hallmarks of neointima lesions are smooth muscle cell proliferation and extracellular matrix deposition.9Schwartz SM deBlois D O'Brien ER The intima. Soil for atherosclerosis and restenosis.Circ Res. 1995; 77: 445-465Crossref PubMed Scopus (897) Google Scholar The pathogenesis of this disease remains poorly understood. Most knowledge concerning the mechanisms of restenosis formation was derived from studies of animal models. In the late 1970s, Clowes and colleagues10Clowes AW Breslow JL Karnovsky MJ Regression of myointimal thickening following carotid endothelial injury and development of aortic foam cell lesions in long term hypercholesterolemic rats.Lab Invest. 1977; 36: 73-81PubMed Google Scholar established the rat arterial injury model, by which a great number of articles describing the process of restenosis were published. In 1993, Lindner and colleagues11Lindner V Fingerle J Reidy MA Mouse model of arterial injury.Circ Res. 1993; 73: 792-796Crossref PubMed Scopus (305) Google Scholar developed the first mouse model of arterial injury using a flexible wire. Subsequently, ligation and electronic injury models were also established.12Kumar A Lindner V Remodeling with neointima formation in the mouse carotid artery after cessation of blood flow.Arterioscler Thromb Vasc Biol. 1997; 17: 2238-2244Crossref PubMed Scopus (434) Google Scholar, 13Carmeliet P Moons L Stassen JM De Mol M Bouche A van den Oord JJ Kockx M Collen D Vascular wound healing and neointima formation induced by perivascular electric injury in mice.Am J Pathol. 1997; 150: 761-776PubMed Google Scholar These models are being widely used by many laboratories and have generated a large number of publications during the last 5 years.14Leidenfrost JE Khan MF Boc KP Villa BR Collins ET Parks WC Abendschein DR Choi ET A model of primary atherosclerosis and post-angioplasty restenosis in mice.Am J Pathol. 2003; 163: 773-778Abstract Full Text Full Text PDF PubMed Scopus (31) Google Scholar, 15Wessely R Hengst L Jaschke B Wegener F Richter T Lupetti R Paschalidis M Schomig A Brandl R Neumann FJ A central role of interferon regulatory factor-1 for the limitation of neointimal hyperplasia.Hum Mol Genet. 2003; 12: 177-187Crossref PubMed Scopus (40) Google Scholar, 16Galis ZS Johnson C Godin D Magid R Shipley JM Senior RM Ivan E Targeted disruption of the matrix metalloproteinase-9 gene impairs smooth muscle cell migration and geometrical arterial remodeling.Circ Res. 2002; 91: 852-859Crossref PubMed Scopus (358) Google Scholar, 17Manka D Collins RG Ley K Beaudet AL Sarembock IJ Absence of p-selectin, but not intercellular adhesion molecule-1, attenuates neointimal growth after arterial injury in apolipoprotein E-deficient mice.Circulation. 2001; 103: 1000-1005Crossref PubMed Scopus (93) Google Scholar, 18Schober A Manka D von Hundelshausen P Huo Y Hanrath P Sarembock IJ Ley K Weber C Deposition of platelet RANTES triggering monocyte recruitment requires P-selectin and is involved in neointima formation after arterial injury.Circulation. 2002; 106: 1523-1529Crossref PubMed Scopus (316) Google Scholar, 19Zimmerman MA Selzman CH Reznikov LL Miller SA Raeburn CD Emmick J Meng X Harken AH Lack of TNF-alpha attenuates intimal hyperplasia after mouse carotid artery injury.Am J Physiol. 2002; 283: R505-R512Google Scholar Because it is difficult to include all of the data derived from the use of these models, a brief summary on several of the models follows (Table 1).Table 1Comparison of Vascular Injury ModelsWire injuryElectronic injuryLigationCollarEC integrityNoNoYesYesMedial injuryYesYesNoNoBlood flowUnchangedUnchangedChangedUnchangedThrombosisSlightlyHeavilyPossiblyNoNeointima+++++++++++Surgery difficulties+++++++EC, endothelial cell. Open table in a new tab Wire-Injury ModelTechnically, this model is similar to that of rat carotid arterial injury. Briefly, the bifurcation of the carotid artery was exposed and two ligations were placed around the external carotid artery, which was then tied off with the distal ligature. An incision hole was made between the two ligatures, where a flexible wire was introduced into the common carotid artery. After passing the vessel three times, Lindner and colleagues11Lindner V Fingerle J Reidy MA Mouse model of arterial injury.Circ Res. 1993; 73: 792-796Crossref PubMed Scopus (305) Google Scholar observed that complete removal of the endothelium was achieved with a flexible wire. A platelet monolayer covered the denuded surface, and damage to underlying medial smooth muscle cells was detected. Injection of [3H]thymidine displayed replication of medial smooth muscle cells, which was found to be 1.6% at 2 days after denudation and 9.8% at 5 days. Smooth muscle cells were observed in the intima by day 8, and by 2 weeks the intimal lesion had a similar cell content as the media. In most animals, repair of the endothelial lining was complete 3 weeks after injury. Using an outbred strain, they found that within 2 weeks after injury, intimal lesions would form in areas that were still denuded. These intimal lesions, however, were not very extensive and usually did not exceed two or three cell layers in thickness.11Lindner V Fingerle J Reidy MA Mouse model of arterial injury.Circ Res. 1993; 73: 792-796Crossref PubMed Scopus (305) Google Scholar, 12Kumar A Lindner V Remodeling with neointima formation in the mouse carotid artery after cessation of blood flow.Arterioscler Thromb Vasc Biol. 1997; 17: 2238-2244Crossref PubMed Scopus (434) Google ScholarCarotid Artery LigationAn alteration in blood flow has been shown to increase intimal lesion formation in vascular grafts and balloon-injured vessels,20Gimbrone Jr, MA Resnick N Nagel T Khachigian LM Collins T Topper JN Hemodynamics, endothelial gene expression, and atherogenesis.Ann NY Acad Sci. 1997; 811: 1-11Crossref PubMed Scopus (105) Google Scholar thus indicating that alterations in biomechanical stress will affect the proliferative response of smooth muscle cells.21Xu Q Biomechanical-stress-induced signaling and gene expression in the development of arteriosclerosis.Trends Cardiovasc Med. 2000; 10: 35-41Abstract Full Text Full Text PDF PubMed Scopus (64) Google Scholar, 22Li C Xu Q Mechanical stress-initiated signal transductions in vascular smooth muscle cells.Cell Signal. 2000; 12: 435-445Crossref PubMed Scopus (257) Google Scholar Furthermore, a number of studies have demonstrated that vessels adapt to chronic changes in blood flow by undergoing compensatory adjustments in their lumen size.23Guyton JR Hartley CJ Flow restriction of one carotid artery in juvenile rats inhibits growth of arterial diameter.Am J Physiol. 1985; 248: H540-H546PubMed Google Scholar, 24Langille BL O'Donnell F Reductions in arterial diameter produced by chronic decreases in blood flow are endothelium-dependent.Science. 1986; 231: 405-407Crossref PubMed Scopus (925) Google Scholar Based on this knowledge, Kumer and Lindner12Kumar A Lindner V Remodeling with neointima formation in the mouse carotid artery after cessation of blood flow.Arterioscler Thromb Vasc Biol. 1997; 17: 2238-2244Crossref PubMed Scopus (434) Google Scholar developed a murine model of carotid artery ligation, in which blood flow in the common carotid artery was disrupted by ligating the vessel near the distal bifurcation. The surgery procedure for this model is relatively simple, ie, ligating the common carotid artery near the bifurcation. Neointimal lesions in the common carotid artery can be seen 2 to 4 weeks after ligation. This model differs from others in that they do not require mechanical trauma and widespread endothelial denudation to induce smooth muscle cell proliferation. It should be noted that the model might not mimic a physiological or pathological situation. However, vascular lesions in humans often develop at sites of altered hemodynamics associated with low shear stress.25Ku DN Giddens DP Zarins CK Glagov S Pulsatile flow and atherosclerosis in the human carotid bifurcation. Positive correlation between plaque location and low oscillating shear stress.Arteriosclerosis. 1985; 5: 293-302Crossref PubMed Google Scholar Therefore, it is conceivable that the factors responsible for intimal lesion formation at these sites might differ from those involved in intimal hyperplasia after arterial injury associated with endothelial denudation. Nevertheless, this model is often used to test the functions of genes in the neointimal formation in knockout mice because of its simplicity.Other Types of Arterial InjuryCarmeliet and colleagues13Carmeliet P Moons L Stassen JM De Mol M Bouche A van den Oord JJ Kockx M Collen D Vascular wound healing and neointima formation induced by perivascular electric injury in mice.Am J Pathol. 1997; 150: 761-776PubMed Google Scholar described a mouse model of carotid artery injury induced by perivascular electric stimulation, in which femoral arteries in mice were injured perivascularly via a single delivery of an electric current. They found that electric injury destroyed all medial smooth muscle cells, denuded the injured segment of intact endothelium, and transiently induced platelet-rich mural thrombosis. A vascular wound-healing response resulted that was characterized by degradation of the mural thrombus, transient infiltration of the vessel wall by inflammatory cells, and progressive removal of the necrotic debris. Topographic analysis revealed repopulation of the media and accumulation in the neointima of smooth muscle cells originating from the uninjured borders and progressing into the necrotic center. Thus, electric injury of arteries provides a model of vascular wound healing with arterial neointima formation and re-endothelialization that may be useful for the genetic analysis of its molecular mechanisms in transgenic mice.In 1989, Booth and colleagues26Booth RF Martin JF Honey AC Hassall DG Beesley JE Moncada S Rapid development of atherosclerotic lesions in the rabbit carotid artery induced by perivascular manipulation.Atherosclerosis. 1989; 76: 257-268Abstract Full Text PDF PubMed Scopus (291) Google Scholar established the rabbit model by placing a perivascular collar resulting in the neointimal formation in the carotid artery. Moroi and colleagues27Moroi M Zhang L Yasuda T Virmani R Gold HK Fishman MC Huang PL Interaction of genetic deficiency of endothelial nitric oxide, gender, and pregnancy in vascular response to injury in mice.J Clin Invest. 1998; 101: 1225-1232Crossref PubMed Scopus (291) Google Scholar adapted this model to mice, in which the left femoral artery was isolated and loosely sheathed with a 2.0-mm polyethylene tube made of PE-50 tubing (inner diameter, 0.56 mm; outer diameter, 0.965 mm) and tied in place with an 8-0 suture. The tube is larger than the vessel, and does not obstruct blood flow. It results in predictable formation of neointima in mice throughout a 14-day period. In this tube model, the endothelial cells are not directly manipulated or removed, allowing study of the effect of individual endothelial factors, including endothelium-derived nitric oxide (NO). In this model, the primary endpoint is neointimal formation, and is complementary to other models. This model has been proven to be reproducible, easily quantitated, and lends itself well to analysis of individual gene products that can be manipulated by transgenic approaches and targeted gene disruption, albeit the mechanism of intimal formation is unknown.Vein Graft AtherosclerosisVascular grafts are widely used in aortocoronary bypass graft surgery.28Davies MG Hagen PO Pathobiology of intimal hyperplasia.Br J Surg. 1994; 81: 1254-1269Crossref PubMed Scopus (372) Google Scholar The small caliber autogenous saphenous vein is usually used as a graft, but occlusion of the graft vein often occurs after bypass operations. A small fraction (perhaps 5 to 10%) of saphenous vein grafts used as aortocoronary bypass vessels occlude within 1 month, ∼10 to 20% occlude within 1 year, and by 10 to 12 years postoperatively, only ∼50 to 60% remain patent. Three pathological processes are primarily responsible for graft occlusion: thrombosis (early closure), intimal hyperplasia (a few months to a few years), and atherosclerosis (usually after 1 year).29Mehta D Izzat MB Bryan AJ Angelini GD Towards the prevention of vein graft failure.Int J Cardiol. 1997; 62: S55-S63Abstract Full Text Full Text PDF PubMed Scopus (76) Google Scholar Understanding the pathogenesis of vein graft atherosclerosis is often extrapolated from studies on (spontaneous) atherosclerosis in arteries, but the features of the lesions and the pathogenic processes of graft-induced atherosclerosis differ from spontaneous atherosclerosis. Therefore, appropriate mouse models for vein grafts would be needed for studying this disease.Technical Feasibility of the Mouse ModelBefore the first mouse model of vein graft arteriosclerosis was successfully established, we tested several methods to anastomose the ends of the vein segment and arteries, including using a suture, a nylon membrane, a plastic tube, and a cuff. Finally, we found that only a cuff technique is feasible to obtain a reproducible result30Zou Y Dietrich H Hu Y Metzler B Wick G Xu Q Mouse model of venous bypass graft arteriosclerosis.Am J Pathol. 1998; 153: 1301-1310Abstract Full Text Full Text PDF PubMed Scopus (201) Google Scholar (Figure 1). Because the vein graft procedure was previously described in detail,30Zou Y Dietrich H Hu Y Metzler B Wick G Xu Q Mouse model of venous bypass graft arteriosclerosis.Am J Pathol. 1998; 153: 1301-1310Abstract Full Text Full Text PDF PubMed Scopus (201) Google Scholar here I just briefly describe the method and include a 3-minute movie (supplement), which would be helpful for the investigators who wish to use this model. When you watch the movie, you see that the right common carotid artery was mobilized free from the bifurcation at the distal end toward the proximal, cut in the middle, and a cuff placed at the end. The cuff was made of an autoclavable nylon tube 0.63 mm in diameter outside and 0.5 mm inside. The artery was turned inside out over the cuff and ligated. The vessel segment of either vena cava or jugular vein from donor was grafted between the two ends of the carotid artery by sleeving the ends of the vein over the artery cuff and ligating them together with the 8-0 suture. As displayed in the movie, pulsation can be seen after removing the clamps. The complete grafting procedure required 30 to 40 minutes.This simplified mouse model of vein grafts has several advantages: first, the operation procedure is simple and easy to learn. The vast majority of investigators could perform the surgery after a short period of training. Second, the traumatic and ischemic injuries to the grafts are minimal. Half an hour is needed to perform the whole operation by our trained surgeon, and the ischemia time of artery segments is between 5 to 10 minutes. Third, the successful rate of surgery is higher because the operation is performed in the neck region and takes a shorter time. Finally, two types of donor organs, jugular vein and vena cava, have been grafted into carotid arteries in the present experiments. Although accelerated arteriosclerosis develops in both vein grafts, the following differences exist. Vena cava is relatively easy to be sleeved over the cuff, which can be used for grafting the vessel donated by another mouse in a same strain or littermate. Because it is an isograft, the role of the specific gene tested in the disease development could be distinguished between the vessel wall and the host, eg, apoE−/− vena cava grafted to an apoE+/+ recipient. Therefore, both donor organs can be used for vein grafts and the technique is feasible for the investigators.The Pathogenesis of Vein Graft AtherosclerosisWith the help of the mouse model, it is possible to understand the cellular and molecular mechanisms of vein graft atherosclerosis. It was demonstrated that one of the earliest cellular events in neointima formation in arteriosclerosis is cell death, in which biomechanical stress is a critical initiator.31Mayr M Li C Zou Y Huemer U Hu Y Xu Q Biomechanical stress-induced apoptosis in vein grafts involves p38 mitogen-activated protein kinases.FASEB J. 2000; 14: 261-270PubMed Google Scholar After cell death, massive mononuclear cell infiltration into the vessel wall occurs. The mechanism by which monocytes/macrophages are continuously recruited to the neointima of the vessel wall may involve two factors: Biomechanical stress directly stimulating endothelial cell and smooth muscle cell expression of adhesion molecules and chemokines; secondly dead cells may be an additional force for the induction of inflammatory responses in the vessel wall.21Xu Q Biomechanical-stress-induced signaling and gene expression in the development of arteriosclerosis.Trends Cardiovasc Med. 2000; 10: 35-41Abstract Full Text Full Text PDF PubMed Scopus (64) Google Scholar Eventually, cell differentiation, proliferation, and accumulation in the intima progress. In this process, biomechanical stress activates platelet-derived growth factor receptor-MAPK pathways, leading to cell proliferation.22Li C Xu Q Mechanical stress-initiated signal transductions in vascular smooth muscle cells.Cell Signal. 2000; 12: 435-445Crossref PubMed Scopus (257) Google Scholar Additional factors stimulating cell growth could be cytokines and growth factors released from inflammatory cells. Finally, vein graft atheroma could be observed in vein grafts performed in apoE−/−32Dietrich H Hu Y Zou Y Huemer U Metzler B Li C Mayr M Xu Q Rapid development of vein graft atheroma in ApoE-deficient mice.Am J Pathol. 2000; 157: 659-669Abstract Full Text Full Text PDF PubMed Scopus (66) Google Scholar or apoE*3-Leiden33Lardenoye JH de Vries MR Lowik CW Xu Q Dhore CR Cleutjens JP van Hinsbergh VW van Bockel JH Quax PH Accelerated atherosclerosis and calcification in vein grafts: a study in APOE*3 Leiden transgenic mice.Circ Res. 2002; 91: 577-584Crossref PubMed Scopus (54) Google Scholar transgenic mice, which are morphologically similar to the lesion in humans (Figure 2).Figure 2Morphology of neointimal and atherosclerotic lesions of vein grafts in mice. Vena cava (a, b) of the mouse was grafted into carotid arteries of wild-type (c, d) or apoE−/− (e, f) mice. Animals were sacrificed 8 weeks after surgery, and the grafted tissue fragments fixed, embedded in paraffin, sectioned, and stained with H&E. Arrows indicate the surface of vessel intima. Note that a proportion of lesions is shown in d and f.View Large Image Figure ViewerDownload Hi-res image Download (PPT)Based on the knowledge of the cellular processes obtained using the mouse model, we could then test the role of specific genes in the pathogenesis of atherosclerosis. For instance, mice lacking transcription factor p53, which is crucial in cell apoptosis, developed neointimal lesions in vein grafts with a twofold increase compared to wild-type controls.34Mayr U Mayr M Li C Wernig F Dietrich H Hu Y Xu Q Loss of p53 accelerates neointimal lesions of vein bypass grafts in mice.Circ Res. 2002; 90: 197-204Crossref PubMed Scopus (76) Google Scholar Importantly, vascular cell apoptosis was significantly reduced in p53−/− vein grafts, which coincided with oxidative DNA damage in vein grafts. In cultured smooth muscle cells from p53−/− mice, apoptosis was increased in response to the death receptor ligand tumor necrosis factor-α, but decreased in response to the NO donor sodium nitroprusside, suggesting that different signaling pathways are involved in tumor necrosis factor-α- and NO-induced apoptosis, respectively.35Mayr M Hu Y Hainaut H Xu Q Mechanical stress-induced DNA damage and rac-p38MAPK signal pathways mediate p53-dependent apoptosis in vascular smooth muscle cells.FASEB J. 2002; 16: 1423-1425Crossref PubMed Scopus (121) Google Scholar Recent observations have shown that upstream activators of p53 were involving p38 MAPK-integrin pathways in mechanical stress-induced apoptosis.36Wernig F Xu Q Mechanical stress-induced apoptosis in cardiovascular system.Prog Biophys Mol Biol. 2002; 78: 105-137Crossref PubMed Scopus (52) Google Scholar, 37Wernig F Mayr M Xu Q Mechanical stretch-induced apoptosis in smooth muscle cells is mediated by beta1-integrin signaling pathways.Hypertension. 2003; 41: 903-911Crossref PubMed Scopus (111) Google ScholarMechanical stretch has a critical role in lesion formation and so Lardenoye et al38Lardenoye JH De Vries MR Grimbergen JM Havekes LM Knaapen MW Kockx MM van Hinsbergh VW van Bockel JH Quax PH Inhibition of accelerated atherosclerosis in vein grafts by placement of external stent in apoE*3-Leiden transgenic mice.Arterioscler Thromb Vasc Biol. 2002; 22: 1433-1438Crossref PubMed Scopus (29) Google Scholar investigated the effect of using an external stent to reduce wall stress. The result was more than 80% reduction in vein graft atherosclerosis and less vascular cell apoptosis. Cell death in vein grafts is followed by an inflammatory response during which expression of endothelial molecules, eg, ICAM-1. When vein grafts were performed in ICAM-1 knockout mice, a 50% reduction of arteriosclerotic lesions was seen. Similarly, interruption of cell migration and proliferation by locally applied drugs, eg, suramin,39Hu Y Zou Y Dietrich H Wick G Xu Q Inhibition of neointima hyperplasia of mouse vein grafts by locally applied suramin.Circulation. 1999; 100: 861-868Crossref PubMed Scopus (120) Google Scholar and gene transfer, e" @default.
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• W36424441 title "Mouse Models of Arteriosclerosis" @default.
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