Systemic VEGF inhibition accelerates experimental atherosclerosis and disrupts endothelial homeostasis - implications for cardiovascular safety

作者：Winnik Stephan; Lohmann Christine; Siciliani Giovanni; von Lukowicz Tobias; Kuschnerus Kira; Kraenkel Nicolle; Brokopp Chad E; Enseleit Frank; Michels Stephan; Ruschitzka Frank; Luescher Thomas F; Matter Christian M^*

来源：International Journal of Cardiology, 2013, 168(3): 2453-2461.

DOI：10.1016/j.ijcard.2013.03.010

• Angiogenesis inhibitors
• Adverse effects
• Cardiovascular diseases
• Patient safety

Objectives: This study sought to examine the effects and underlying mechanisms of systemic VEGF inhibition in experimental atherosclerosis and aortic endothelial cells. %26lt;br%26gt;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. %26lt;br%26gt;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, 50 mg/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. %26lt;br%26gt;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. %26lt;br%26gt;Conclusion: 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.

• 出版日期2013-10-3