Salt Sensitivity of Angiogenesis Inhibition–Induced Blood Pressure Rise

Angiogenesis, the formation of new vessels from preexisting vasculature, is critical to tumor growth and metastasis. This process is regulated by numerous factors, with vascular endothelial growth factor (VEGF) playing a predominant role. Different strategies to inhibit the VEGF signaling pathway by directly targeting VEGF or blocking its receptors have been developed and have become established modalities for the treatment of a wide range of malignancies. VEGF inhibition is associated with hypertension, proteinuria, and renal function impairment in a substantial proportion of patients, sometimes necessitating discontinuation of treatment. Sunitinib is an orally active angiogenesis inhibitor that blocks the VEGF receptors (VEGFR)-1, -2 and -3 and other tyrosine kinase receptors, including platelet-derived growth factor and c-Kit receptors, by interacting with their ATP-binding pockets. VEGFR-1 and VEGFR-2 are predominantly expressed on vascular endothelial cells, whereas VEGFR-3, stimulated by VEGF-C, is mainly restricted to lymphatic endothelial cells. A previous study has shown that the multitargeted VEGFR inhibitor SU5416 enhances dietary salt–induced hypertension and kidney injury in normotensive Sprague–Dawley rats. The authors speculated that the SU5416-induced decrease in renal nitric oxide (NO) production in proximal tubular epithelial cells via inhibition of endothelial NO synthase underlies this salt-sensitive hypertension. Recent reports indicate that in response to a high-salt diet (HSD), Na and Cl accumulate in the skin in excess of water. This results in a hypertonic interstitial fluid compartment and accumulation of mononuclear phagocyte system (MPS) cells. In response to the hypertonic environment, MPS cells secrete increased amounts of VEGF-C in a tonicity-responsive enhancer-binding protein (TonEBP), also known as nuclear factor of activated T-cells 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. (Hypertension. 2017;69:919-926. DOI: 10.1161/ HYPERTENSIONAHA.116.08565.) • Online Data Supplement