Cited by 688Atherosclerosis and Cardiovascular DiseasesCerebrovascular and Carotid Artery DiseasesCholesterol and Lipid Metabolism

Angiogenesis Inhibitors Endostatin or TNP-470 Reduce Intimal Neovascularization and Plaque Growth in Apolipoprotein E–Deficient Mice

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Moulton, Karen S., Heller, Eric, Konerding, Moritz A., Flynn, Evelyn, Palinski, Wulf, Folkman, Judah·1999·Circulation

Abstract

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 mm 2 (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 mm 2 (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.

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Crossref · 10.1161/01.cir.99.13.1726

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  • Small-molecule drugs such as TNP-470, endostatin or angiostatin reduced plaque angiogenesis and inhibited advanced atherosclerosis in APOE-knockout mice after 16 weeks of treatment.

    “Small-molecule drugs like the fumagillin analogue TNP-470, endostatin or angiostatin reduced plaque angiogenesis and inhibited advanced atherosclerosis in APOE-knockout mice after prolonged treatment for 16 weeks105,106.”

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Authors
Moulton, K. S., Heller, E., Konerding, M. A., Flynn, E., Palinski, W., & Folkman, J.
Affiliations
Brigham and Women's Hospital (US)
Venue
Circulation
Published
1999-04-06
Volume
99
Issue
13
Pages
1726-1732
ISSN
  • 0009-7322 (ISSN-L)
  • 1524-4539
OpenAlex
W2152639592
Cited by
688
References
26
Citations by year
2026: 3 · 2025: 3 · 2024: 3 · 2023: 10 · 2022: 15 · 2021: 10 · 2020: 11 · 2019: 8 · 2018: 10 · 2017: 21 · 2016: 20 · 2015: 17 · 2014: 23 · 2013: 21 · 2012: 19
FWCI
16.63
Type
journal article
Language
en
Open access
Locations
  • Circulation (publishedVersion)
  • PubMed (publishedVersion)
  • eScholarship (California Digital Library) (submittedVersion)
Funders
  • National Institutes of Health (5k11hl002563-06)
  • National Heart, Lung, and Blood Institute (K11-HL02563)
Topics
  • Life Sciences › Immunology and Microbiology › Immunology › Atherosclerosis and Cardiovascular Diseases
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Cerebrovascular and Carotid Artery Diseases
  • Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
Keywords
angiogenesis inhibitors, endostatin, TNP-470, atherosclerotic plaque growth, ApoE-deficient mice, atherosclerosis progression, smooth muscle cells, cholesterol diet
MeSH terms
O-(Chloroacetylcarbamoyl)fumagillol, Animals, Aorta, Thoracic, Apolipoproteins E, Cell Count, Cell Division, Collagen, Cyclohexanes, Male, Muscle, Smooth, Vascular, Neovascularization, Pathologic, Peptide Fragments, Sesquiterpenes, Time Factors, Tunica Intima, Mice, Knockout, Endostatins, Mice

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