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Blood, 1 January 2007, Vol. 109, No. 1, pp. 122-129. Prepublished online as a Blood First Edition Paper on September 21, 2006; DOI 10.1182/blood-2006-07-031773.
HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY Vascular endothelial growth factor-A induces plaque expansion in ApoE knock-out mice by promoting de novo leukocyte recruitment1 Leiden/Amsterdam Center for Drug Research, Leiden University, The Netherlands; 2 Institute for Molecular Cardiovascular Research, University Hospital, Rheinisch-Westfälische Technische Hochschule, Aachen, Germany; 3 A. I. Virtanen Institute of Molecular Sciences, University of Kuopio, Finland; and 4 Medical University Vienna, Center of Biomolecular Medicine and Pharmacology, Department of Vascular Biology and Thrombosis Research, Vienna, Austria
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-Abased 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-Atreated 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-1dependent 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-1directed cotherapy may be an efficient strategy to prevent bystander effects of focal VEGF-A therapy in patients suffering from cardiovascular disease.
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