2. Academic Validation
  3. Macrophages regulate salt-dependent volume and blood pressure by a vascular endothelial growth factor-C-dependent buffering mechanism

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

Affiliation

  • 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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