(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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|
|
|
|
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|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
 |
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
Y. Cao, A. Hong, H. Schulten, and M. J. Post Update on therapeutic neovascularization Cardiovasc Res, February 15, 2005; 65(3): 639 - 648. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
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|
|
|
|
 |
|
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|
|
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|
 |
|
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|
|
|
|
 |
|
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|
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|
|
|
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|
|
|
|
|
|
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|
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|
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