VEGFR (Vascular Endothelial Growth Factor Receptor) Inhibition Induces Cardiovascular Damage via Redox-Sensitive Processes

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 (Ser 1177 ) phosphorylation and reduced NO and H 2 O 2 production, responses associated with increased Nox-derived O 2 − 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 2+ influx and MLC 20 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.