P319	Adenoviral mediated overexpression of VEGF leads to a vulnerable plaque phenotype in ApoE-deficient mice.
1M.Lucerna, 1R.de Nooijer, 2A.Zernecke, 1I.Bot, 1S.de Jager, 1T.van Berkel, 2Chr.Weber, 1E.Biessen
1Institute of Biopharmaceutics, Leiden, NL; 2Department of Molecular Cardiovascular Research, Aachen, DE.

Objective: VEGF, a potent angiogenic factor, binds selectively to VEGFR1 and VEGFR2 on endothelial cells inducing neovascularization, and to VEGFR1 on macrophages leading to chemotactic response. In this study we examine the effect of an adenoviral-mediated overexpression of VEGF in the atherosclerotic plaque. Methods: Plaque formation was induced by collar placement on the carotid arteries of ApoE-/- mice fed a high cholesterol diet. 4 weeks after surgery the resulting plaques were incubated transluminally with recombinant adenovirus carrying either VEGF cDNA (n=8) or no transgene (n=8). 2 weeks later mice were sacrificed and analyzed the carotid artery plaques for morphology and histology. In a subsequent experiment we analyzed in more detail macrophage recruitment by intravital microscopy using the same experimental setup (n=3). Results: VEGF overexpression was found lead to an increased plaque size by 25 % (p<0.05). The macrophage content was significantly increased by 15 % (p<0.05), the collagen content significantely decreased (p<0.03) in VEGF-treated animals, and the plaque displayed a more vulnerable phenotype (p<0.013). Surprisingly, VEGF overexpression did not lead to a significant induction of microvessel development in the plaque, suggesting that VEGF might destabilze plaques through an angiogenesis-independent effect. Intravital microscopy revealed that VEGF increased leukocyte recruitment/adhesion to the atherosclerotic plaque by 2.5 fold, which could be blocked by inhibition of adhesion molecules like VLA-4, PECAM and ICAM but not JAM-1. Conclusion: VEGF promotes a more vulnerable plaque phenotype, which is influenced by an undirect effect on the expression of inflammatory molecules on endothelial cells, resulting in a dramatic increase of macrophage influx. Blocking the bioavailability of these molecules influences the angiogenic input on plaque progression in mice.

Copyright © 2005 S. Karger AG, Basel. Any further use of this abstract requires written permission from the publisher.