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Related Experiment Video

Updated: Jun 18, 2026

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VEGF inhibitor-induced vascular dysfunction involves redox-sensitive PARP activation and SIRT1 disruption.

Karla B Neves1,2, Rheure Alves-Lopes2,3, Augusto C Montezano2,4

  • 1Strathclyde Institute of Pharmacy & Biomedical Sciences, University of Strathclyde, Glasgow, UK.

Experimental Physiology
|June 17, 2026
PubMed
Summary

Vascular endothelial growth factor receptor (VEGFR) inhibitors cause vascular injury via oxidative stress and poly(ADP-ribose) polymerase (PARP) activation, leading to sirtuin 1 (SIRT1) downregulation. Targeting PARP or boosting SIRT1 may prevent these side effects.

Keywords:
PARP activationVEGFR inhibitionendothelial dysfunctionoxidative stresssirtuin 1vascular inflammation

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Area of Science:

  • Cardiovascular Biology
  • Molecular Oncology
  • Pharmacology

Background:

  • Vascular endothelial growth factor receptor (VEGFR) inhibitors are crucial in cancer therapy but induce cardiovascular toxicities like hypertension and vascular dysfunction.
  • The underlying molecular mechanisms of these toxicities remain unclear, with oxidative stress implicated.

Purpose of the Study:

  • To investigate the roles of redox-sensitive poly(ADP-ribose) polymerase (PARP) and sirtuin 1 (SIRT1) in VEGFR inhibitor-induced vascular injury.
  • To explore potential therapeutic strategies targeting these pathways.

Main Methods:

  • Molecular studies using axitinib (VEGFR inhibitor)-treated human aortic endothelial cells.
  • Vascular function assessments in isolated mouse arteries.
  • Measurement of reactive oxygen species, PARP activation, SIRT1 activity, endothelial nitric oxide synthase (eNOS) phosphorylation, and inflammatory markers.

Main Results:

  • Axitinib increased reactive oxygen species, PARP activation, and inhibitory eNOS phosphorylation at Thr495, while reducing SIRT1 activity and increasing p53 acetylation.
  • These effects were mitigated by antioxidants, PARP inhibitors (olaparib), or SIRT1 activators (SRT1720).
  • VEGFR inhibition promoted vascular inflammation and dysfunction, which were attenuated by PARP inhibition or SIRT1 activation.

Conclusions:

  • VEGFR inhibition triggers oxidative stress and PARP activation, subsequently downregulating SIRT1, leading to endothelial dysfunction and vascular inflammation.
  • Targeting PARP activation or enhancing SIRT1 activity shows promise for mitigating VEGFR inhibitor-associated vascular complications.