Macrophages regulate salt-dependent volume and blood pressure by a vascular endothelial growth factor-C–dependent buffering mechanism

A Machnik, W Neuhofer, J Jantsch, A Dahlmann… - Nature medicine, 2009 - nature.com
A Machnik, W Neuhofer, J Jantsch, A Dahlmann, T Tammela, K Machura, JK Park, FX Beck…
Nature medicine, 2009nature.com
In salt-sensitive hypertension, the accumulation of Na+ in tissue has been presumed to be
accompanied by a commensurate retention of water to maintain the isotonicity of body fluids.
We show here that a high-salt diet (HSD) in rats leads to interstitial hypertonic Na+
accumulation in skin, resulting in increased density and hyperplasia of the lymphcapillary
network. The mechanisms underlying these effects on lymphatics involve activation of
tonicity-responsive enhancer binding protein (TonEBP) in mononuclear phagocyte system …
Abstract
In salt-sensitive hypertension, the accumulation of Na+ in tissue has been presumed to be accompanied by a commensurate retention of water to maintain the isotonicity of body fluids. We show here that a high-salt diet (HSD) in rats leads to interstitial hypertonic Na+ accumulation in skin, resulting in increased density and hyperplasia of the lymphcapillary network. The mechanisms underlying these effects on lymphatics involve activation of tonicity-responsive enhancer binding protein (TonEBP) in mononuclear phagocyte system (MPS) cells infiltrating the interstitium of the skin. TonEBP binds the promoter of the gene encoding vascular endothelial growth factor-C (VEGF-C, encoded by Vegfc) and causes VEGF-C secretion by macrophages. MPS cell depletion or VEGF-C trapping by soluble VEGF receptor-3 blocks VEGF-C signaling, augments interstitial hypertonic volume retention, decreases endothelial nitric oxide synthase expression and elevates blood pressure in response to HSD. Our data show that TonEBP–VEGF-C signaling in MPS cells is a major determinant of extracellular volume and blood pressure homeostasis and identify VEGFC as an osmosensitive, hypertonicity-driven gene intimately involved in salt-induced hypertension.
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