In response to salt loading, Na+ and Cl- accumulate in the skin in excess of water, stimulating skin lymphangiogenesis via activation of the mononuclear phagocyte system cell-derived vascular endothelial growth factor-C-vascular endothelial growth factor type 3 receptor signaling pathway. Inhibition of this pathway results in salt-sensitive hypertension. Sunitinib is an antiangiogenic, anticancer agent that blocks all 3 vascular endothelial growth factor receptors and increases blood pressure. We explored the salt dependency of sunitinib-induced hypertension and whether impairment of skin lymphangiogenesis is an underlying mechanism. Normotensive Wistar-Kyoto rats were exposed to a normal or high salt with or without sunitinib administration. Sunitinib induced a 15 mm Hg rise in telemetrically measured blood pressure, which was aggravated by a high-salt diet (HSD), resulting in a decline of the slope of the pressure-natriuresis curve. Without affecting body weight, plasma Na+ concentration or renal function, Na+ and Cl- skin content increased by 31% and 32% with the high salt and by 49% and 50% with the HSD plus sunitinib, whereas skin water increased by 17% and 24%, respectively. Skin mononuclear phagocyte system cell density increased both during sunitinib and a HSD, but no further increment was seen when HSD and sunitinib were combined. HSD increased skin lymphangiogenesis, while sunitinib tended to decrease lymphangiogenesis, both during a normal-salt diet and HSD. We conclude that sunitinib induces hypertension that is aggravated by high salt intake and not accompanied by impaired skin lymphangiogenesis.

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Keywords angiogenesis inhibition, hypertension, lymphangiogenesis, Na+ storage, salt sensitivity, sunitinib, vascular endothelial growth factor
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Journal Hypertension
Lankhorst, S, Severs, D, Markó, L. (Lajos), Rakova, N. (Natalia), Titze, J. (Jens), Müller, D.N. (Dominik N.), … van den Meiracker, A.H. (2017). Salt Sensitivity of Angiogenesis Inhibition-Induced Blood Pressure Rise: Role of Interstitial Sodium Accumulation?. Hypertension, 69(5), 919–926. doi:10.1161/HYPERTENSIONAHA.116.08565