Vascular endothelial growth factor-A induces plaque expansion in ApoE knock-out mice by promoting de novo leukocyte recruitment

Blood. 2007 Jan 1;109(1):122-9. doi: 10.1182/blood-2006-07-031773. Epub 2006 Sep 21.


Vascular endothelial growth factor-A is widely used in clinical trials for the treatment of cardiac ischemia. VEGF-A was recently suggested to act in a proinflammatory manner, which could aggravate adjacent atherogenesis in VEGF-A-based therapy. To assess potential bystander effects, VEGF-A was focally overexpressed in advanced atherosclerotic plaques in ApoE-/- mice. Sheer-induced carotid artery plaques were transluminally incubated with Ad.hVEGF-A leading to neointimal overexpression of VEGF-A. Ad.hVEGF-A treatment of pre-existing lesions was seen to promote plaque expansion, with a concomitant increase in macrophage and lipid content, whereas it lowered collagen content. In general, Ad.hVEGF-A-treated plaques displayed a more vulnerable phenotype. VEGF-A overexpression was not accompanied by increased microvessel development in the neointima, suggesting that VEGF-A destabilizes atherosclerotic plaques through an angiogenesis-independent mechanism. Intravital microscopy confirmed that treatment with Ad.hVEGF-A led to an increased monocyte adhesion, which was mediated by a VCAM-1/PECAM-1-dependent pathway. VEGF-A indeed induced a differential expression of VCAM-1 and PECAM-1 in endothelial cells. Our data underline the importance of regular monitoring of stenotic vessels adjacent to the site of VEGF-A application. We propose that VCAM-1/PECAM-1-directed cotherapy may be an efficient strategy to prevent bystander effects of focal VEGF-A therapy in patients suffering from cardiovascular disease.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenoviridae / genetics
  • Animals
  • Apolipoproteins E / deficiency
  • Autocrine Communication
  • Carotid Artery Diseases / etiology
  • Carotid Artery Diseases / metabolism
  • Carotid Artery Diseases / pathology*
  • Cell Adhesion
  • Cells, Cultured
  • Chemotaxis / physiology*
  • Collagen / analysis
  • Endothelial Cells / metabolism
  • Endothelium, Vascular / cytology
  • Female
  • Gene Expression
  • Genetic Vectors / pharmacology
  • Humans
  • Inflammation
  • Lipids / analysis
  • Macrophages / pathology*
  • Mice
  • Mice, Knockout
  • Monocytes / pathology*
  • Neovascularization, Physiologic / drug effects
  • Paracrine Communication
  • Platelet Endothelial Cell Adhesion Molecule-1 / physiology
  • Recombinant Fusion Proteins / physiology
  • Reverse Transcriptase Polymerase Chain Reaction
  • Tunica Intima / metabolism
  • Tunica Intima / pathology
  • Vascular Cell Adhesion Molecule-1 / physiology
  • Vascular Endothelial Growth Factor A / genetics
  • Vascular Endothelial Growth Factor A / physiology*
  • Vascular Endothelial Growth Factor A / toxicity


  • Apolipoproteins E
  • Lipids
  • Platelet Endothelial Cell Adhesion Molecule-1
  • Recombinant Fusion Proteins
  • VEGFA protein, human
  • Vascular Cell Adhesion Molecule-1
  • Vascular Endothelial Growth Factor A
  • Collagen