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

Abstract

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.

• Authors: Markus Lucerna, Alma Zernecke, Ramon de Nooijer, Saskia C de Jager, Ilze Bot, Christian van der Lans, Ivana Kholova, Elisa A Liehn, Theo J C van Berkel, Seppo Yla-Herttuala, Christian Weber, Eric A L Biessen
• Journal: Blood (Blood) Vol. 109 Issue 1 Pg. 122-9 (Jan 01 2007) ISSN: 0006-4971 [Print] United States
• PMID: 16990600 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 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

Topics

• Adenoviridae (genetics)
• Animals
• Apolipoproteins E (deficiency)
• Autocrine Communication
• Carotid Artery Diseases (etiology, metabolism, 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, pathology)
• Vascular Cell Adhesion Molecule-1 (physiology)
• Vascular Endothelial Growth Factor A (genetics, physiology, toxicity)