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

Neves, Karla B. and Rios, Francisco J. and Van Der Mey, Lucas and Alves-Lopes, Rheure and Cameron, Alan C. and Volpe, Massimo and Montezano, Augusto C. and Savoia, Carmine and Touyz, Rhian M. (2018) VEGFR (vascular endothelial growth factor receptor) inhibition induces cardiovascular damage via redox-sensitive processes. Hypertension, 71 (4). pp. 638-647. ISSN 1524-4563 (https://doi.org/10.1161/HYPERTENSIONAHA.117.10490)

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Abstract

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 (Ser1177) phosphorylation and reduced NO and H2O2 production, responses associated with increased Nox-derived O2 - 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 Ca2+ influx and MLC20 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.

ORCID iDs

Neves, Karla B. ORCID logoORCID: https://orcid.org/0000-0001-5158-9263, Rios, Francisco J., Van Der Mey, Lucas, Alves-Lopes, Rheure, Cameron, Alan C., Volpe, Massimo, Montezano, Augusto C., Savoia, Carmine and Touyz, Rhian M.;
  • Item type:Article
    ID code:82960
    Dates:
    Date
    Event
    28 February 2018
    Published
    23 January 2018
    Accepted
    Notes:Funding Information: This study was funded by grants from the British Heart Foundation (BHF) (RE/13/5/30177) and Research Award, Sapienza University of Rome. R.M. Touyz is supported by a BHF Chair (CH/12/429762). C. Savoia was supported by Fondazione Roma (NCDS-2013-00000345) and the Italian Ministry of Education, University and Research (PRIN-2015ZTT5KB 003). Publisher Copyright: © 2018 American Heart Association, Inc.
    Subjects:Medicine
    Department:Faculty of Science > Strathclyde Institute of Pharmacy and Biomedical Sciences
    Depositing user: Pure Administrator
    Date deposited:27 Oct 2022 13:30
    Last modified:20 Nov 2024 20:24
    Related URLs:
    URI:https://strathprints.strath.ac.uk/id/eprint/82960
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