Axitinib-induced VEGFR inhibition causes oxidative stress and PARP activation, leading to SIRT1 downregulation, endothelial dysfunction, and vascular inflammation.
VEGFR inhibitor-induced vascular dysfunction is mediated by oxidative stress and PARP activation leading to SIRT1 downregulation, suggesting PARP inhibitors or SIRT1 activators could mitigate these cardiovascular toxicities.
Abstract Vascular endothelial growth factor receptor (VEGFR) inhibitors are effective antiangiogenic agents used in cancer therapy. However, they are associated with cardiovascular disease, including hypertension and vascular dysfunction. The molecular mechanisms underlying these cardiovascular toxicities are unclear, but oxidative stress might be important. Here we investigated the potential role of redox‐sensitive poly(ADP‐ribose) polymerase (PARP) and sirtuin 1 (SIRT1) in VEGFR inhibitor‐induced vascular injury. Molecular studies were performed in axitinib (VEGFR inhibitor)‐treated human aortic endothelial cells, and vascular studies were undertaken in isolated intact vessels from mice. Axitinib increased reactive oxygen species production and PARP activation. This was prevented by tiron (antioxidant) and olaparib (PARP inhibitor). Phosphorylation of endothelial nitric oxide synthase at Thr 495 (inhibitory site) was increased and activity of SIRT1 was reduced following axitinib treatment. This was accompanied by increased p53 acetylation; these effects were mitigated by olaparib or the SIRT1 activator SRT1720. VEGFR inhibition increased expression and secretion of pro‐inflammatory markers (MCP‐1 and interleukin‐6) and adhesion molecules (VCAM‐1 and ICAM‐1) and promoted THP‐1 monocyte adhesion to human aortic endothelial cells, effects that were attenuated by PARP inhibition or SIRT1 activation. In isolated arteries, axitinib enhanced contractile responses to U46619 and endothelin‐1 while impairing ACh‐induced relaxation. Co‐treatment with olaparib or SRT1720 restored vascular responses and endothelial nitric oxide synthase phosphorylation. In conclusion, inhibition of VEGFR signalling induces oxidative stress and PARP activation, leading to SIRT1 downregulation, endothelial dysfunction and vascular inflammation. Targeting PARP activation or enhancing SIRT1 activity might represent promising strategies to mitigate VEGF inhibitor‐induced vascular complications.
Neves et al. (Wed,) conducted a other in VEGFR inhibitor-induced vascular injury. Axitinib (VEGFR inhibitor) vs. Control / co-treatment with olaparib or SRT1720 was evaluated on Vascular dysfunction, oxidative stress, PARP activation, and SIRT1 activity. Axitinib-induced VEGFR inhibition causes oxidative stress and PARP activation, leading to SIRT1 downregulation, endothelial dysfunction, and vascular inflammation.