Abstract
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.
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Acknowledgements
This work was supported by the National Natural Science Foundation of China (Grants 81870370, 81930009, and 91639202 to ZRZ), the 2017–2018 Annual Special Fund for Scientific Research and Transformation of Heilongjiang Academy of Medical Sciences (CR201810), and the Nn10 Program of Harbin Medical University Cancer Hospital.
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ZCD, BZ, and ZRZ contributed to the conception and design of the research. ZCD, CL, YLZ, XY, CC, and XH carried out the experiments. ZCD, QSW, CL, YLZ, XY, LXZ, CC, and XH performed the data acquisition and analyzed the data. ZCD wrote the paper. BZ, MMW, and ZRZ reviewed and critically revised the paper. We are particularly grateful to Professor Hui-hua Li for his guidance and help in the experiment and paper writing. All authors read and approved the final paper and agree to be accountable for all aspects of the research in ensuring that the accuracy and integrity of all parts of the work are appropriately investigated and resolved.
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Dong, Zc., Wu, Mm., Zhang, Yl. et al. The vascular endothelial growth factor trap aflibercept induces vascular dysfunction and hypertension via attenuation of eNOS/NO signaling in mice. Acta Pharmacol Sin 42, 1437–1448 (2021). https://doi.org/10.1038/s41401-020-00569-1
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DOI: https://doi.org/10.1038/s41401-020-00569-1
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