VEGFR (vascular endothelial growth factor receptor) inhibition induces cardiovascular damage via redox-sensitive processes

Neves, K. B. , Rios, F. J. , Van Der Mey, L., Alves-Lopes, R. , Cameron, A. C., Volpe, M., Montezano, A. C., Savoia, C. and Touyz, R. M. (2018) VEGFR (vascular endothelial growth factor receptor) inhibition induces cardiovascular damage via redox-sensitive processes. Hypertension, 71(4), pp. 638-647. (doi: 10.1161/HYPERTENSIONAHA.117.10490) (PMID:29483228)

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Although VEGF (vascular endothelial growth factor) inhibitors (VEGFIs), are effective anticancer therapies, they cause hypertension through unknown mechanisms. We questioned whether changes in vascular redox state may be important, because VEGF signaling involves nitric oxide (NO) and reactive oxygen species. Molecular mechanisms, including NOS, NADPH oxidase (Nox)-derived reactive oxygen species, antioxidant systems, and vasoconstrictor signaling pathways, were probed in human endothelial cells and vascular smooth muscle exposed to vatalanib, a VEGFI. Vascular functional effects of VEGFI were assessed ex vivo in mouse arteries. Cardiovascular and renal in vivo effects were studied in vatalanib- or gefitinib (EGFI [epidermal growth factor inhibitor])-treated mice. In endothelial cells, vatalanib decreased eNOS (Ser ) phosphorylation and reduced NO and H O production, responses associated with increased Nox-derived O and ONOO formation. Inhibition of Nox1/4 (GKT137831) or Nox1 (NoxA1ds), prevented vatalanib-induced effects. Nrf-2 (nuclear factor erythroid 2-related factor 2) nuclear translocation and expression of Nrf-2-regulated antioxidant enzymes were variably downregulated by vatalanib. In human vascular smooth muscles, VEGFI increased Nox activity and stimulated Ca influx and MLC phosphorylation. Acetylcholine-induced vasodilatation was impaired and U46619-induced vasoconstriction was enhanced by vatalanib, effects normalized by N-acetyl-cysteine and worsened by L-NAME. In vatalanib-, but not gefitinib-treated mice vasorelaxation was reduced and media:lumen ratio of mesenteric arteries was increased with associated increased cardiovascular and renal oxidative stress, decreased Nrf-2 activity and downregulation of antioxidant genes. We demonstrate that inhibition of VEGF signaling induces vascular dysfunction through redox-sensitive processes. Our findings identify Noxs and antioxidant enzymes as novel targets underling VEGFI-induced vascular dysfunction. These molecular processes may contribute to vascular toxicity and hypertension in VEGFI-treated patients.

Item Type:Articles
Keywords:Endothelial cells, gefitinib, reactive oxygen species, vasodilation, vatalanib.
Glasgow Author(s) Enlighten ID:Rios, Dr Francisco and Van Der Mey, Mr Lucas and Alves Moreira Lopes, Dr Rheure and Savoia, Professor Carmine and Cameron, Dr Alan and Montezano, Dr Augusto and Neves, Dr Karla and Touyz, Professor Rhian
Authors: Neves, K. B., Rios, F. J., Van Der Mey, L., Alves-Lopes, R., Cameron, A. C., Volpe, M., Montezano, A. C., Savoia, C., and Touyz, R. M.
College/School:College of Medical Veterinary and Life Sciences > School of Cardiovascular & Metabolic Health
Journal Name:Hypertension
Publisher:American Heart Association
ISSN (Online):1524-4563
Published Online:26 February 2018
Copyright Holders:Copyright © 2018 American Heart Association, Inc.
First Published:First published in Hypertension 71(4): 638-647
Publisher Policy:Reproduced in accordance with the publisher copyright policy

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
617771BHF centre of excellenceRhian TouyzBritish Heart Foundation (BHF)RE/13/5/30177RI CARDIOVASCULAR & MEDICAL SCIENCES
607381Vascular Noxs as therapeutic targets and biomarkers in hypertensionRhian TouyzBritish Heart Foundation (BHF)CH/12/4/29762RI CARDIOVASCULAR & MEDICAL SCIENCES