title: Systemic VEGF inhibition accelerates experimental atherosclerosis and disrupts endothelial homeostasis--implications for cardiovascular safety.
abstract: OBJECTIVE
  This study sought to examine the effects and underlying mechanisms of systemic VEGF inhibition in experimental atherosclerosis and aortic endothelial cells.
  
  
  BACKGROUND
  Pharmacological inhibition of vascular endothelial growth factor (VEGF), a major mediator of angiogenesis, has become a widely applied treatment of certain cancers and multiple ocular diseases including age-related macular degeneration. However, recent clinical trials raise concern for systemic vascular adverse effects, prompting the Food and Drug Administration to revoke the approval of bevacizumab for metastatic breast cancer.
  
  
  METHODS
  Eight-week old apolipoprotein E knockout mice received a high-cholesterol diet (1.25% cholesterol) for 24 weeks and were exposed to a systemic pan-VEGF receptor inhibitor (PTK787/ZK222584, 50mg/kg/d) or placebo (gavage) for the last 10 weeks. Atherosclerotic lesions were characterized in thoraco-abdominal aortae and aortic arches. Mechanistic analyses were performed in cultured human aortic endothelial cells.
  
  
  RESULTS
  Systemic VEGF inhibition increased atherosclerotic lesions by 33% whereas features of plaque vulnerability (i.e. necrotic core size, fibrous cap thickness) remained unchanged compared with controls. Aortic eNOS expression was decreased (trend). In human endothelial cells VEGF inhibition induced a dose-dependent increase in mitochondrial superoxide generation with an uncoupling of eNOS, resulting in reduced NO availability and decreased proliferation.
  
  
  CONCLUSIONS
  Systemic VEGF inhibition disrupts endothelial homeostasis and accelerates atherogenesis, suggesting that these events contribute to the clinical cardiovascular adverse events of VEGF-inhibiting therapies. Cardiovascular safety profiles of currently applied anti-angiogenic regimens should be determined to improve patient selection for therapy and allow close monitoring of patients at increased cardiovascular risk.
authors.affiliation: Division of Cardiology, University Hospital Zurich, Zurich, Switzerland; Cardiovascular Research, Institute of Physiology, University of Zurich, Zurich, Switzerland.
authors.forename: Stephan
authors.initials: S
authors.lastname: Winnik
authors.forename: Christine
authors.initials: C
authors.lastname: Lohmann
authors.forename: Giovanni
authors.initials: G
authors.lastname: Siciliani
authors.forename: Tobias
authors.initials: T
authors.lastname: von Lukowicz
authors.forename: Kira
authors.initials: K
authors.lastname: Kuschnerus
authors.forename: Nicolle
authors.initials: N
authors.lastname: Kraenkel
authors.forename: Chad E
authors.initials: CE
authors.lastname: Brokopp
authors.forename: Frank
authors.initials: F
authors.lastname: Enseleit
authors.forename: Stephan
authors.initials: S
authors.lastname: Michels
authors.forename: Frank
authors.initials: F
authors.lastname: Ruschitzka
authors.forename: Thomas F
authors.initials: TF
authors.lastname: Lüscher
authors.forename: Christian M
authors.initials: CM
authors.lastname: Matter
mesh_terms: D020533:Angiogenesis Inhibitors / Q000009:adverse effects*; D000818:Animals; D050197:Atherosclerosis / Q000139:chemically induced*; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000503:physiopathology*; D006706:Homeostasis; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010793:Phthalazines / Q000009:adverse effects*; D011725:Pyridines / Q000009:adverse effects*; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors*
chemical_list: D020533:Angiogenesis Inhibitors; D010793:Phthalazines; D011725:Pyridines; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; C404768:vatalanib
keywords: Adverse effects; Angiogenesis inhibitors; Cardiovascular diseases; Patient safety