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

Proc Natl Acad Sci U S A. 2003 Apr 15;100(8):4736-41. doi: 10.1073/pnas.0730843100. Epub 2003 Apr 7.


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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Angiostatins
  • Animals
  • Apolipoproteins E / deficiency
  • Apolipoproteins E / genetics
  • Arteriosclerosis / etiology
  • Arteriosclerosis / pathology*
  • Arteriosclerosis / prevention & control*
  • Chemokine CCL2 / biosynthesis
  • Endothelial Growth Factors / biosynthesis
  • Endothelial Growth Factors / pharmacology
  • Feedback
  • In Vitro Techniques
  • Inflammation / pathology
  • Intercellular Signaling Peptides and Proteins / biosynthesis
  • Intercellular Signaling Peptides and Proteins / pharmacology
  • Lymphokines / biosynthesis
  • Lymphokines / pharmacology
  • Macrophages / drug effects
  • Macrophages / pathology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Monocytes / drug effects
  • Monocytes / pathology
  • Neovascularization, Pathologic / prevention & control*
  • Peptide Fragments / biosynthesis
  • Peptide Fragments / pharmacology
  • Plasminogen / biosynthesis
  • Plasminogen / pharmacology
  • Receptors, LDL / deficiency
  • Receptors, LDL / genetics
  • Vasa Vasorum / pathology
  • Vascular Endothelial Growth Factor A
  • Vascular Endothelial Growth Factors


  • 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