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

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.