Updated in 1/17/2017 5:38:58 PM |
Viewed: 1747 times |
(Journal Article) |
Nature medicine 15 (5): 545-52 (2009)
Macrophages regulate salt-dependent volume and blood pressure by a vascular endothelial growth factor-C-dependent buffering mechanism.
Agnes Machnik
,
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
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.