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

  • Nat Med. 2009 May;15(5):545-52. doi: 10.1038/nm.1960.
Agnes Machnik  1 ,  Wolfgang Neuhofer ,  Jonathan Jantsch ,  Anke Dahlmann ,  Tuomas Tammela ,  Katharina Machura ,  Joon-Keun Park ,  Franz-Xaver Beck ,  Dominik N Müller ,  Wolfgang Derer ,  Jennifer Goss ,  Agata Ziomber ,  Peter Dietsch ,  Hubertus Wagner ,  Nico van Rooijen ,  Armin Kurtz ,  Karl F Hilgers ,  Kari Alitalo ,  Kai-Uwe Eckardt ,  Friedrich C Luft ,  Dontscho Kerjaschki ,  Jens Titze
Affiliations
  • 1. Department of Nephrology and Hypertension, and Nikolaus Fiebiger Centre for Molecular Medicine, University Clinic and Friedrich Alexander University of Erlangen-Nuremberg, Germany.
PMID: 19412173 DOI: 10.1038/nm.1960
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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