(Circulation. 1999;99:1726-1732.)
© 1999 American Heart Association, Inc.
Basic Science Reports |
Angiogenesis Inhibitors Endostatin or TNP-470 Reduce Intimal Neovascularization and Plaque Growth in Apolipoprotein E–Deficient Mice
From the Surgical Research Laboratory (K.S.M., E.F., J.F.), Children's Hospital, Boston Mass; Cardiovascular Division (K.S.M.), Brigham and Women's Hospital, Boston, Mass; Harvard Medical School (E.H.), Boston, Mass; the Department of Anatomy (M.A.K.), University of Mainz, Mainz, Germany; and the Department of Medicine (W.P.), University of California, San Diego, Calif.
Correspondence to Karen S. Moulton, Children's Hospital, Surgical Research Laboratory Enders 10, 300 Longwood Ave, Boston, MA 02115. E-mail moulton{at}hub.tch.harvard.edu
Background—Neovascularization within the intima of human atherosclerotic lesions is well described, but its role in the progression of atherosclerosis is unknown. In this report, we first demonstrate that intimal vessels occur in advanced lesions of apolipoprotein E–deficient (apoE -/-) mice. To test the hypothesis that intimal vessels promote atherosclerosis, we investigated the effect of angiogenesis inhibitors on plaque growth in apoE -/- mice.
Methods and Results—ApoE -/- mice were fed a 0.15%
cholesterol diet. At age 20 weeks, mice were divided into 3
groups and treated for 16 weeks as follows: group 1, recombinant mouse
endostatin, 20 mg · kg-1 · d-1;
group 2, fumagillin analogue TNP-470, 30 mg/kg every other day; and
group 3, control animals that received a similar volume of buffer.
Average cholesterol levels were similar in all groups.
Plaque areas were quantified at the aortic origin. Median plaque area
before treatment was 0.250 mm2 (range, 0.170 to 0.348;
n=10). Median plaque areas were 0.321 (0.238 to 0.412; n=10), 0.402
(0.248 to 0.533; n=15), and 0.751 mm2 (0.503 to 0.838;
n=12) for the endostatin, TNP-470, and control groups, respectively
(P
0.0001). Therefore, endostatin and TNP-470 inhibited
plaque growth during the treatment period by 85% and 70%. Intimal
smooth muscle cell contents of plaques from control and treated mice
were similar.
Conclusions—Prolonged treatment with either angiogenesis inhibitor reduced plaque growth and intimal neovascularization in apoE -/- mice. Although the mechanism of plaque inhibition induced by these agents is not established, these results suggest that intimal neovascularization may promote plaque development.
Key Words: angiogenesis • atherosclerosis • apolipoproteins
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R. Khurana, S. Shafi, J. Martin, and I. Zachary Vascular Endothelial Growth Factor Gene Transfer Inhibits Neointimal Macrophage Accumulation in Hypercholesterolemic Rabbits Arterioscler. Thromb. Vasc. Biol., June 1, 2004; 24(6): 1074 - 1080. [Abstract] [Full Text] [PDF]
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K. S. Meir and E. Leitersdorf Atherosclerosis in the Apolipoprotein E-Deficient Mouse: A Decade of Progress Arterioscler. Thromb. Vasc. Biol., June 1, 2004; 24(6): 1006 - 1014. [Abstract] [Full Text] [PDF]
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J. K. Liao Statin Therapy: Having the Good Without the Bad Hypertension, June 1, 2004; 43(6): 1171 - 1172. [Full Text] [PDF]
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C. R. Wolfram Kuhlmann, C. Gast, F. Li, M. Schafer, H. Tillmanns, B. Waldecker, and J. Wiecha Cerivastatin Activates Endothelial Calcium-Activated Potassium Channels and Thereby Modulates Endothelial Nitric Oxide Production and Cell Proliferation J. Am. Soc. Nephrol., April 1, 2004; 15(4): 868 - 875. [Abstract] [Full Text] [PDF]
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 J. R. Kizer, D. A. Zisman, N. P. Blumenthal, R. M. Kotloff, S. E. Kimmel, R. M. Strieter, S. M. Arcasoy, V. A. Ferrari, and J. Hansen-Flaschen Association Between Pulmonary Fibrosis and Coronary Artery Disease Arch Intern Med, March 8, 2004; 164(5): 551 - 556. [Abstract] [Full Text] [PDF]
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C. Calvi, P. Dentelli, M. Pagano, A. Rosso, M. Pegoraro, S. Giunti, G. Garbarino, G. Camussi, L. Pegoraro, and M. F. Brizzi Angiopoietin 2 Induces Cell Cycle Arrest in Endothelial Cells: A Possible Mechanism Involved in Advanced Plaque Neovascularization Arterioscler. Thromb. Vasc. Biol., March 1, 2004; 24(3): 511 - 518. [Abstract] [Full Text]
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E. Brakenhielm, N. Veitonmaki, R. Cao, S. Kihara, Y. Matsuzawa, B. Zhivotovsky, T. Funahashi, and Y. Cao Adiponectin-induced antiangiogenesis and antitumor activity involve caspase-mediated endothelial cell apoptosis PNAS, February 24, 2004; 101(8): 2476 - 2481. [Abstract] [Full Text] [PDF]
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A. Paul, K. W.S. Ko, L. Li, V. Yechoor, M. A. McCrory, A. J. Szalai, and L. Chan C-Reactive Protein Accelerates the Progression of Atherosclerosis in Apolipoprotein E-Deficient Mice Circulation, February 10, 2004; 109(5): 647 - 655. [Abstract] [Full Text] [PDF]
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J. J. Khatri, C. Johnson, R. Magid, S. M. Lessner, K. M. Laude, S. I. Dikalov, D. G. Harrison, H.-J. Sung, Y. Rong, and Z. S. Galis Vascular Oxidant Stress Enhances Progression and Angiogenesis of Experimental Atheroma Circulation, February 3, 2004; 109(4): 520 - 525. [Abstract] [Full Text] [PDF]
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Y. Numaguchi, K. Okumura, M. Harada, K. Naruse, M. Yamada, H. Osanai, H. Matsui, M. Ito, and T. Murohara Catheter-based prostacyclin synthase gene transfer prevents in-stent restenosis in rabbit atheromatous arteries Cardiovasc Res, January 1, 2004; 61(1): 177 - 185. [Abstract] [Full Text] [PDF]
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M. Ii and D. W. Losordo Transplant Graft Vasculopathy: A Dark Side of Bone Marrow Stem Cells? Circulation, December 23, 2003; 108(25): 3056 - 3058. [Full Text] [PDF]
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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]
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K. Pels, C. Deiner, S. E Coupland, M. Noutsias, A. P Sutter, H.-P. Schultheiss, S. Yla-Herttuala, and P. L Schwimmbeck Effect of adventitial VEGF165 gene transfer on vascular thickening after coronary artery balloon injury Cardiovasc Res, December 1, 2003; 60(3): 664 - 672. [Abstract] [Full Text] [PDF]
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D. V Baklanov, K. G Peters, A. L Seidel, D. A Taylor, and B. H Annex Neovascularization in intimal hyperplasia is associated with vein graft failure after coronary artery bypass surgery Vascular Medicine, August 1, 2003; 8(3): 163 - 167. [Abstract] [PDF]
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 M. H. DEININGER, W. A. WYBRANIETZ, F. T.C. GRAEPLER, U. M. LAUER, R. MEYERMANN, and H. J. SCHLUESENER Endothelial endostatin release is induced by general cell stress and modulated by the nitric oxide/cGMP pathway FASEB J, July 1, 2003; 17(10): 1267 - 1276. [Abstract] [Full Text] [PDF]
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D. W. Losordo, J. M. Isner, and L. J. Diaz-Sandoval Endothelial Recovery: The Next Target in Restenosis Prevention Circulation, June 3, 2003; 107(21): 2635 - 2637. [Full Text] [PDF]
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K. S. Moulton, K. Vakili, D. Zurakowski, M. Soliman, C. Butterfield, E. Sylvin, K.-M. Lo, S. Gillies, K. Javaherian, and J. Folkman Inhibition of plaque neovascularization reduces macrophage accumulation and progression of advanced atherosclerosis PNAS, April 15, 2003; 100(8): 4736 - 4741. [Abstract] [Full Text] [PDF]
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R. Hutter, B. V. Sauter, E. D. Reis, M. Roque, D. Vorchheimer, F. E. Carrick, J. T. Fallon, V. Fuster, and J. J. Badimon Decreased Reendothelialization and Increased Neointima Formation With Endostatin Overexpression in a Mouse Model of Arterial Injury Circulation, April 1, 2003; 107(12): 1658 - 1663. [Abstract] [Full Text] [PDF]
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P. Libby and D. X.-M. Zhao Allograft Arteriosclerosis and Immune-Driven Angiogenesis Circulation, March 11, 2003; 107(9): 1237 - 1239. [Full Text] [PDF]
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N. van Royen, I. Hoefer, M. Bottinger, J. Hua, S. Grundmann, M. Voskuil, C. Bode, W. Schaper, I. Buschmann, and J.J. Piek Local Monocyte Chemoattractant Protein-1 Therapy Increases Collateral Artery Formation in Apolipoprotein E-Deficient Mice but Induces Systemic Monocytic CD11b Expression, Neointimal Formation, and Plaque Progression Circ. Res., February 7, 2003; 92(2): 218 - 225. [Abstract] [Full Text] [PDF]
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P.O Bonetti, L.O Lerman, C Napoli, and A Lerman Statin effects beyond lipid lowering--are they clinically relevant? Eur. Heart J., February 1, 2003; 24(3): 225 - 248. [Full Text] [PDF]
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N van Royen, I Hoefer, I Buschmann, S Kostin, M Voskuil, C. Bode, W Schaper, and J.J Piek Effects of local MCP-1 protein therapy on the development of the collateral circulation and atherosclerosis in Watanabe hyperlipidemic rabbits Cardiovasc Res, January 1, 2003; 57(1): 178 - 185. [Abstract] [Full Text] [PDF]
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 M. H. Deininger, B. A. Fimmen, D. R. Thal, H. J. Schluesener, and R. Meyermann Aberrant Neuronal and Paracellular Deposition of Endostatin in Brains of Patients with Alzheimer's Disease J. Neurosci., December 15, 2002; 22(24): 10621 - 10626. [Abstract] [Full Text] [PDF]
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A. Hilfiker, D. Hilfiker-Kleiner, M. Fuchs, K. Kaminski, A. Lichtenberg, H.-J. Rothkotter, B. Schieffer, and H. Drexler Expression of CYR61, an Angiogenic Immediate Early Gene, in Arteriosclerosis and Its Regulation by Angiotensin II Circulation, July 9, 2002; 106(2): 254 - 260. [Abstract] [Full Text] [PDF]
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