OBJECTIVES: 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. 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.
OBJECTIVES: 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. 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.
Authors: Frank Enseleit; Stephan Michels; Isabella Sudano; Marc Stahel; Sandrine Zweifel; Oliver Schlager; Matthias Becker; Stephan Winnik; Matthias Nägele; Andreas J Flammer; Michel Neidhart; Nicole Graf; Christian M Matter; Burkhardt Seifert; Thomas F Lüscher; Frank Ruschitzka Journal: Ophthalmologica Date: 2017-09-02 Impact factor: 3.250
Authors: Joerg Herrmann; Eric H Yang; Cezar A Iliescu; Mehmet Cilingiroglu; Konstantinos Charitakis; Abdul Hakeem; Konstantinos Toutouzas; Massoud A Leesar; Cindy L Grines; Konstantinos Marmagkiolis Journal: Circulation Date: 2016-03-29 Impact factor: 29.690
Authors: Mirela Tuzovic; Joerg Herrmann; Cezar Iliescu; Kostas Marmagkiolis; Boback Ziaeian; Eric H Yang Journal: Curr Treat Options Cardiovasc Med Date: 2018-04-07