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Nitric oxide depletion is responsible for the adverse effects of vascular endothelial growth factor inhibitors

Nature Clinical Practice Nephrology volume 4, pages 536–537 (2008)Cite this article

Vascular endothelial growth factor (VEGF) is an important mediator of angiogenesis, a process thought to have a critical role in the growth of tumors and in the progression of other diseases that rely on neovascularization. Anti-VEGF therapies such as bevacizumab have, therefore, recently been introduced as treatments for these conditions. However, as the use of VEGF inhibitors has spread, so have observations of serious adverse effects including hypertension, proteinuria and renal thrombotic microangiopathy.1 The cause of these adverse events has not yet been identified, but I believe that nitric oxide (NO), an important mediator of the angiogenic effects of VEGF, is the primary suspect.

Papapetropoulos et al. were the first to prove that VEGF stimulates NO production in cultured endothelial cells.2 Exposure of human umbilical vein endothelial cells to VEGF led to a concentration-dependent increase in NO production, which was effected by VEGF recruitment of the second messenger cyclic guanosine monophosphate. Long-term exposure of these cells to VEGF stimulated NO synthesis through an increase in the levels of endothelial NO synthase. Short-term VEGF exposure induced release of NO by activation of tyrosine and phosphoinositide kinases.

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  1. University of Liverpool, Haematology Department, Prescot Street, Liverpool L7 8XP, UK jeckothachil@yahoo.co.uk

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  1. J Thachil is a Clinical Research Fellow at the University of Liverpool, Liverpool, UK.,

    Jecko Thachil

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Thachil, J. Nitric oxide depletion is responsible for the adverse effects of vascular endothelial growth factor inhibitors. Nat Rev Nephrol 4, 536–537 (2008). https://doi.org/10.1038/ncpneph0907

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