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. Epub 2009 May 3.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blood Pressure / physiology*
  • Homeostasis
  • Hypertension / chemically induced
  • Hypertension / physiopathology*
  • Macrophages / physiology*
  • Mice
  • Phagocytes / drug effects
  • Phagocytes / physiology
  • Rats
  • Receptors, Vascular Endothelial Growth Factor / physiology
  • Signal Transduction
  • Skin / drug effects
  • Skin Physiological Phenomena
  • Sodium Chloride / adverse effects*
  • Sodium, Dietary / adverse effects*
  • Transcription Factors / physiology*
  • Vascular Endothelial Growth Factor C / antagonists & inhibitors
  • Vascular Endothelial Growth Factor C / physiology*


  • Nfat5 protein, rat
  • Sodium, Dietary
  • Transcription Factors
  • Vascular Endothelial Growth Factor C
  • Sodium Chloride
  • Receptors, Vascular Endothelial Growth Factor