title: 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.affiliation: Leiden/Amsterdam Center for Drug Research, Leiden University, Einsteinweg 55, 2333 CC Leiden, The Netherlands.
authors.forename: Markus
authors.initials: M
authors.lastname: Lucerna
authors.forename: Alma
authors.initials: A
authors.lastname: Zernecke
authors.forename: Ramon
authors.initials: R
authors.lastname: de Nooijer
authors.forename: Saskia C
authors.initials: SC
authors.lastname: de Jager
authors.forename: Ilze
authors.initials: I
authors.lastname: Bot
authors.forename: Christian
authors.initials: C
authors.lastname: van der Lans
authors.forename: Ivana
authors.initials: I
authors.lastname: Kholova
authors.forename: Elisa A
authors.initials: EA
authors.lastname: Liehn
authors.forename: Theo J C
authors.initials: TJ
authors.lastname: van Berkel
authors.forename: Seppo
authors.initials: S
authors.lastname: Yla-Herttuala
authors.forename: Christian
authors.initials: C
authors.lastname: Weber
authors.forename: Eric A L
authors.initials: EA
authors.lastname: Biessen
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency; D019898:Autocrine Communication; D002340:Carotid Artery Diseases / Q000209:etiology / Q000378:metabolism / Q000473:pathology*; D002448:Cell Adhesion; D002478:Cells, Cultured; D002633:Chemotaxis / Q000502:physiology*; D003094:Collagen / Q000032:analysis; D042783:Endothelial Cells / Q000378:metabolism; D004730:Endothelium, Vascular / Q000166:cytology; D005260:Female; D015870:Gene Expression; D005822:Genetic Vectors / Q000494:pharmacology; D006801:Humans; D007249:Inflammation; D008055:Lipids / Q000032:analysis; D008264:Macrophages / Q000473:pathology*; D051379:Mice; D018345:Mice, Knockout; D009000:Monocytes / Q000473:pathology*; D018919:Neovascularization, Physiologic / Q000187:drug effects; D019899:Paracrine Communication; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000502:physiology; D011993:Recombinant Fusion Proteins / Q000502:physiology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017539:Tunica Intima / Q000378:metabolism / Q000473:pathology; D019010:Vascular Cell Adhesion Molecule-1 / Q000502:physiology; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000502:physiology* / Q000633:toxicity
chemical_list: D001057:Apolipoproteins E; D008055:Lipids; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D011993:Recombinant Fusion Proteins; C467484:VEGFA protein, human; D019010:Vascular Cell Adhesion Molecule-1; D042461:Vascular Endothelial Growth Factor A; D003094:Collagen