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Salt sensitivity of angiogenesis inhibition-induced blood pressure rise: role of interstitial sodium accumulation?

Item Type:Article
Title:Salt sensitivity of angiogenesis inhibition-induced blood pressure rise: role of interstitial sodium accumulation?
Creators Name:Lankhorst, S. and Severs, D. and Markó, L. and Rakova, N. and Titze, J. and Müller, D.N. and Danser, A.H.J. and van den Meiracker, A.H.
Abstract: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.
Keywords:Angiogenesis Inhibition, Hypertension, Lymphangiogenesis, Na+ Storage, Salt Sensitivity, Sunitinib, Vascular Endothelial Growth Factor, Animals, Rats
Publisher:American Heart Association
Page Range:919-926
Date:May 2017
Official Publication:https://doi.org/10.1161/HYPERTENSIONAHA.116.08565
PubMed:View item in PubMed

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