Aflibercept,as a soluble decoy vascular endothelial growth factor receptor,Which has been used as a first-line monotherapy for cancers.Aflibercept often causes cardiovascular toxicities including hypertension,but the mechanisms underlying aflibercept-induced hypertension remain unknown.In this study we investigated the effect of short-term and long-term administration of aflibercept on blood pressure (BP),vascular function,NO bioavailability,oxidative stress and endothelin 1 (ET-1) in mice and cultured endothelial cells.We showed that injection of a single-dose of aflibercept (18.2,36.4 mg/kg,iv) rapidly and dose-dependently elevated BP in mice.Aflibercept treatment markedly impaired endothelial-dependent relaxation (EDR) and resulted in NADPH oxidases 1 (NOX1)-and NADPH oxidases 4 (NOX4)-mediated generation of ROS,decreased the activation of protein kinase B (Akt) and endothelial nitric oxide synthase (eNOS) concurrently with a reduction in nitric oxide (NO) production and elevation of ET-1 levels in mouse aortas;these effects were greatly attenuated by supplementation of L-arginine (L-arg,0.5 or 1.0 g/kg,bid,ig)before aflibercept injection.Similar results were observed in L-arg-pretreated cultured endothelial cells,showing markedly decreased ROS accumulation and AKT/eNOS/NO signaling impairment induced by aflibercept.In order to assess the effects of long-term aflibercept on hypertension and to evaluate the beneficial effects of L-arg supplementation,we administered these two drugs to WT mice for up to 14 days (at an interval of two days).Long-term administration of aflibercept resulted in a sustained increase in BP and a severely impaired EDR,which are associated with NOX1/NOX4-mediated production of ROS,increase in ET-1,inhibition of AKT/eNOS/NO signaling and a decreased expression of cationic amino acid transporter (CAT-1).The effects caused by long-term administration were greatly attenuated by L-arg supplementation in a dose-dependent manner.We conclude that aflibercept leads to vascular dysfunction and hypertension by inhibiting CAT-1/AKT/eNOS/NO signaling,increasing ET-1,and activating NOX1/NOX4-mediated oxidative stress,which can be suppressed by supplementation of L-arg.Therefore,L-arg could be a potential therapeutic agent for aflibercept-induced hypertension.