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Building a Better Mouse Model
J Mol Cell Cardiol 32, 1921–1922 (2000) doi:10.1006/jmcc.2000.1248, available online at http://www.idealibrary.com on
Editorial
Building a Better Mouse Model Kenneth Walsh Division of Cardiovascular Research, St. Elizabeth’s Medical Center, and the Program in Cell, Molecular and Developmental Biology, Sackler School of Biomedical Studies, Tufts University School of Medicine, 736 Cambridge Street, Boston, MA 02135, USA The ability to construct “designer” mice through genetic manipulation holds great promise for understanding disease processes at a molecular level. However, the mouse can be a poor model of human pathologies, not only due to inherent differences in physiology but also as a result of its small size. These issues are especially problematic in studies of vascular pathophysiology. In their brief communication in this issue of Journal of Molecular and Cellular Cardiology, Sata et al.1 describe a more reproducible wire model of vascular injury that better mimics the pathological features of balloon angioplasty. As such, it represents a technological breakthrough in this area of investigation and should permit a genetic dissection of the processes that regulate intimal hyperplasia. A murine “wire” model of arterial injury was first described by Lindner et al.2 In this original model the common carotid artery is denuded of endothelium using a curved flexible wire. Unfortunately, this method suffers from the shortcoming of not producing a reliable neointimal lesion. In some instances, a small intimal lesion is formed by this injury, but most often smooth muscle hyperplasia occurs within the medial layer, which is of questionable clinical relevance.3 In the experiments of Sata et al.,1 a relatively large, straight spring wire is used to distend and denude the endothelium of the mouse femoral artery. This procedure, while similar to the mouse vascular injury model reported by Roque et al.,4 involves insertion of the wire through a small muscular branch of the femoral artery thereby preserving blood flow across the site of injury, a feature lacking in the earlier method. Similar to acute balloon injury models in rat, rabbit and pig, this new mouse injury model produces a rapid decrease in cellularity within the media due to apoptotic cell death.5 At one week post-injury, proliferating cells appear in 0022–2828/00/111921+02 $35.00/0
the media and a small neointima is detectable. By three weeks post-injury, a robust neointimal lesion has formed with an intima-to-media area ratio of approximately 2.0. By four weeks post-injury reendothelialization is largely complete and the lesion ceases to grow. The lesion is comprised primarily of smooth muscle cells, although sparse macrophages could be detected in the neointima and the adventitia. Of particular significance, this method of injury is reported to induce a reproducible lesion in four different strains of mice, some of which are commonly employed in transgenic and knock-out studies. Other mouse models of vascular injury have been developed that cause vascular disruption through perivascular delivery of an electric current,6 photochemical induction of endothelial disruption7 or airdesiccation and distention.8 In these models the injury ablates vascular cells and produces intimal lesions comprised of smooth muscle cells by two weeks. These procedures have provided insights about the pathophysiology of vascular remodeling, but they suffer from questionable relevance with regard to the injury that occurs following balloon injury. Still other mouse models involve the complete cessation of blood flow of the carotid artery near the bifurcation9 or placement of a perivascular cuff.10 These models do not recapitulate cellular processes associated with post-angioplasty restenosis, but instead result in a neointimal lesion that forms beneath an intact endothelium. Therefore, such models have a useful purpose through providing a capability for evaluating the role of perturbed leukocyte–endothelium interactions on lesion formation.11,12 It appears that a number of useful new tools are in place and detailed genetic analyses of the molecular processes involved in vascular lesion formation should be forthcoming. These injury 2000 Academic Press
1922
K. Walsh
models, when used in conjunction with the large number of mutant and transgenic mouse lines that exist today, should allow dissection of the relative contributions of smooth muscle proliferation and apoptosis, re-endothelialization and inflammatory processes in neointima formation following vascular injury.
References 1. S M, M Y, A F, F K, S A, S S, A T, I Y, K H, K K, O M, M M, H Y, N R. A mouse model of vascular injury that induces rapid onset of medial cell apoptosis followed by reproducible neointimal hyperplasia. J Mol Cell Cardiol 2000; 32: 2097–2104. 2. L V, F J, R MA. Mouse model of arterial injury. Circ Res 1993; 73: 792–796. 3. I MD, K RH, A M, K S, S J TR, L DB, O’D J TF, K KS, M ME. Estrogen inhibits the vascular injury response in estrogen receptor alpha-deficient mice. Nature Med 1997; 3: 545–548. 4. R M, F JT, B JJ, Z WX, T MB, R ED. Mouse model of femoral artery denudation injury associated with the rapid accumulation of adhesion molecules on the luminal surface and recruitment of neutrophils. Arterioscler Thromb Vasc Biol 2000; 20: 335–342.
5. W K, S RC, K HS. Vascular cell apoptosis in remodeling, restenosis and plaque rupture. Circ Res 2000; 87: 184–188. 6. C P, M L, S J-M, D M M, B A, O JJ, K M, C D. Vascular wound healing and neointima formation induced by perivascular electric injury in mice. Am J Path 1997; 150: 761–776. 7. K S, U K, K K, S AR, N M. Photochemically induced endothelial injury in the mouse as a screening model for inhibitors of vascular intimal thickening. Arterioscler Thromb Vasc Biol 1998; 18: 1069–1078. 8. S DI, D Z, S P, E ER, B CM, R C. Decreased neointimal formation in Mac-1(-/-) mice reveals a role for inflammation in vascular repair after angioplasty. J Clin Invest 2000; 105: 293–300. 9. K A, L V. Remodeling with neointima formation in the mouse carotid artery after cessation of blood flow. Arterioscler Thromb Vasc Biol 1997; 17: 2238–2244. 10. M M, Z L, Y T, V R, G HK, F MC, H PL. Interaction of genetic deficiency of endothelial nitric oxide, gender, and pregnancy in vascular response to injury in mice. J Clin Invest 1998; 101: 1225–1232. 11. K A, H JL, S CA, L V, S RJ. Remodeling and neointima formation in the carotid artery of normal and P-selectin-deficient mice. Circulation 1997; 96: 4333–4342. 12. S M, W K. Fas ligand-deficient mice display enhanced leukocyte infiltration and intima hyperplasia in flow-restricted vessels. J Mol Cell Cardiol 2000; 32: 1395–1400.
Editorial
Building a Better Mouse Model Kenneth Walsh Division of Cardiovascular Research, St. Elizabeth’s Medical Center, and the Program in Cell, Molecular and Developmental Biology, Sackler School of Biomedical Studies, Tufts University School of Medicine, 736 Cambridge Street, Boston, MA 02135, USA The ability to construct “designer” mice through genetic manipulation holds great promise for understanding disease processes at a molecular level. However, the mouse can be a poor model of human pathologies, not only due to inherent differences in physiology but also as a result of its small size. These issues are especially problematic in studies of vascular pathophysiology. In their brief communication in this issue of Journal of Molecular and Cellular Cardiology, Sata et al.1 describe a more reproducible wire model of vascular injury that better mimics the pathological features of balloon angioplasty. As such, it represents a technological breakthrough in this area of investigation and should permit a genetic dissection of the processes that regulate intimal hyperplasia. A murine “wire” model of arterial injury was first described by Lindner et al.2 In this original model the common carotid artery is denuded of endothelium using a curved flexible wire. Unfortunately, this method suffers from the shortcoming of not producing a reliable neointimal lesion. In some instances, a small intimal lesion is formed by this injury, but most often smooth muscle hyperplasia occurs within the medial layer, which is of questionable clinical relevance.3 In the experiments of Sata et al.,1 a relatively large, straight spring wire is used to distend and denude the endothelium of the mouse femoral artery. This procedure, while similar to the mouse vascular injury model reported by Roque et al.,4 involves insertion of the wire through a small muscular branch of the femoral artery thereby preserving blood flow across the site of injury, a feature lacking in the earlier method. Similar to acute balloon injury models in rat, rabbit and pig, this new mouse injury model produces a rapid decrease in cellularity within the media due to apoptotic cell death.5 At one week post-injury, proliferating cells appear in 0022–2828/00/111921+02 $35.00/0
the media and a small neointima is detectable. By three weeks post-injury, a robust neointimal lesion has formed with an intima-to-media area ratio of approximately 2.0. By four weeks post-injury reendothelialization is largely complete and the lesion ceases to grow. The lesion is comprised primarily of smooth muscle cells, although sparse macrophages could be detected in the neointima and the adventitia. Of particular significance, this method of injury is reported to induce a reproducible lesion in four different strains of mice, some of which are commonly employed in transgenic and knock-out studies. Other mouse models of vascular injury have been developed that cause vascular disruption through perivascular delivery of an electric current,6 photochemical induction of endothelial disruption7 or airdesiccation and distention.8 In these models the injury ablates vascular cells and produces intimal lesions comprised of smooth muscle cells by two weeks. These procedures have provided insights about the pathophysiology of vascular remodeling, but they suffer from questionable relevance with regard to the injury that occurs following balloon injury. Still other mouse models involve the complete cessation of blood flow of the carotid artery near the bifurcation9 or placement of a perivascular cuff.10 These models do not recapitulate cellular processes associated with post-angioplasty restenosis, but instead result in a neointimal lesion that forms beneath an intact endothelium. Therefore, such models have a useful purpose through providing a capability for evaluating the role of perturbed leukocyte–endothelium interactions on lesion formation.11,12 It appears that a number of useful new tools are in place and detailed genetic analyses of the molecular processes involved in vascular lesion formation should be forthcoming. These injury 2000 Academic Press
1922
K. Walsh
models, when used in conjunction with the large number of mutant and transgenic mouse lines that exist today, should allow dissection of the relative contributions of smooth muscle proliferation and apoptosis, re-endothelialization and inflammatory processes in neointima formation following vascular injury.
References 1. S M, M Y, A F, F K, S A, S S, A T, I Y, K H, K K, O M, M M, H Y, N R. A mouse model of vascular injury that induces rapid onset of medial cell apoptosis followed by reproducible neointimal hyperplasia. J Mol Cell Cardiol 2000; 32: 2097–2104. 2. L V, F J, R MA. Mouse model of arterial injury. Circ Res 1993; 73: 792–796. 3. I MD, K RH, A M, K S, S J TR, L DB, O’D J TF, K KS, M ME. Estrogen inhibits the vascular injury response in estrogen receptor alpha-deficient mice. Nature Med 1997; 3: 545–548. 4. R M, F JT, B JJ, Z WX, T MB, R ED. Mouse model of femoral artery denudation injury associated with the rapid accumulation of adhesion molecules on the luminal surface and recruitment of neutrophils. Arterioscler Thromb Vasc Biol 2000; 20: 335–342.
5. W K, S RC, K HS. Vascular cell apoptosis in remodeling, restenosis and plaque rupture. Circ Res 2000; 87: 184–188. 6. C P, M L, S J-M, D M M, B A, O JJ, K M, C D. Vascular wound healing and neointima formation induced by perivascular electric injury in mice. Am J Path 1997; 150: 761–776. 7. K S, U K, K K, S AR, N M. Photochemically induced endothelial injury in the mouse as a screening model for inhibitors of vascular intimal thickening. Arterioscler Thromb Vasc Biol 1998; 18: 1069–1078. 8. S DI, D Z, S P, E ER, B CM, R C. Decreased neointimal formation in Mac-1(-/-) mice reveals a role for inflammation in vascular repair after angioplasty. J Clin Invest 2000; 105: 293–300. 9. K A, L V. Remodeling with neointima formation in the mouse carotid artery after cessation of blood flow. Arterioscler Thromb Vasc Biol 1997; 17: 2238–2244. 10. M M, Z L, Y T, V R, G HK, F MC, H PL. Interaction of genetic deficiency of endothelial nitric oxide, gender, and pregnancy in vascular response to injury in mice. J Clin Invest 1998; 101: 1225–1232. 11. K A, H JL, S CA, L V, S RJ. Remodeling and neointima formation in the carotid artery of normal and P-selectin-deficient mice. Circulation 1997; 96: 4333–4342. 12. S M, W K. Fas ligand-deficient mice display enhanced leukocyte infiltration and intima hyperplasia in flow-restricted vessels. J Mol Cell Cardiol 2000; 32: 1395–1400.