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PMID: 12682294 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

Inhibition of plaque neovascularization reduces macrophage accumulation and progression of advanced atherosclerosis.

Proceedings of the National Academy of Sciences of the United States of America ·Vol. 100 ·No. 8 ·2003-04-15 ·Pages 4736-41

Moulton KS, Vakili K, Zurakowski D, Soliman M, Butterfield C, Sylvin E, Lo KM, Gillies S, Javaherian K, Folkman J

Abstract

Plaque angiogenesis promotes the growth of atheromas, but the functions of plaque capillaries are not fully determined. Neovascularization may act as a conduit for the entry of leukocytes into sites of chronic inflammation. We observe vasa vasorum density correlates highly with the extent of inflammatory cells, not the size of atheromas in apolipoprotein E-deficient mice. We show atherosclerotic aortas contain activities that promote angiogenesis. The angiogenesis inhibitor angiostatin reduces plaque angiogenesis and inhibits atherosclerosis. Macrophages in the plaque and around vasa vasorum are reduced, but we detect no direct effect of angiostatin on monocytes. After angiogenesis blockade in vivo, the angiogenic potential of atherosclerotic tissue is suppressed. Activated macrophages stimulate angiogenesis that can further recruit inflammatory cells and more angiogenesis. Our findings demonstrate that late-stage inhibition of angiogenesis can interrupt this positive feedback cycle. Inhibition of plaque angiogenesis and the secondary reduction of macrophages may have beneficial effects on plaque stability.

MeSH Terms
Angiostatins Animals Apolipoproteins E/deficiency,genetics Arteriosclerosis/etiology,pathology,prevention & control Chemokine CCL2/biosynthesis Endothelial Growth Factors/biosynthesis,pharmacology Feedback In Vitro Techniques Inflammation/pathology Intercellular Signaling Peptides and Proteins/biosynthesis,pharmacology Lymphokines/biosynthesis,pharmacology Macrophages/drug effects,pathology Mice Mice, Inbred C57BL Mice, Knockout Monocytes/drug effects,pathology Neovascularization, Pathologic/prevention & control Peptide Fragments/biosynthesis,pharmacology Plasminogen/biosynthesis,pharmacology Receptors, LDL/deficiency,genetics Vasa Vasorum/pathology Vascular Endothelial Growth Factor A Vascular Endothelial Growth Factors
Chemicals
Apolipoproteins E Chemokine CCL2 Endothelial Growth Factors Intercellular Signaling Peptides and Proteins Lymphokines Peptide Fragments Receptors, LDL Vascular Endothelial Growth Factor A Vascular Endothelial Growth Factors Angiostatins Plasminogen
Authors & Affiliations
10 authors, click to expand affiliations / ORCID
Moulton Karen S
Department of Surgery, Children's Hospital Medical Center and Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115, USA. karen.moulton@tch.harvard.edu
Vakili Khashayar
Zurakowski David
Soliman Mohsin
Butterfield Catherine
Sylvin Erik
Lo Kin-Ming
Gillies Stephen
Javaherian Kashi
Folkman Judah
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Article Info
Journal
Proceedings of the National Academy of Sciences of the United States of America
Abbr.
Proc Natl Acad Sci U S A
ISSN
0027-8424
DOI
10.1073/pnas.0730843100
Email
karen.moulton@tch.harvard.edu
Published
2003-04-15
Epub
2003-00-07
Pages
4736-41
Language
English
Region
United States
NLM ID
7505876
PMCID
PMC153625
Subset
IM
Grants
NHLBI NIH HHS · R01 HL067255 · United States
External Links
PubMed source DOI: 10.1073/pnas.0730843100 PMC Full Text View journal details
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