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

Official URL:https://doi.org/10.1038/nm.1960
PubMed:View item in PubMed
Creators Name:Machnik, A. and Neuhofer, W. and Jantsch, J. and Dahlmann, A. and Tammela, T. and Machura, K. and Park, J.K. and Beck, F.X. and Mueller, D.N. and Derer, W. and Goss, J. and Ziomber, A. and Dietsch, P. and Wagner, H. and van Rooijen, N. and Kurtz, A. and Hilgers, K.F. and Alitalo, K. and Eckardt, K.U. and Luft, F.C. and Kerjaschki, D. and Titze, J.
Journal Title:Nature Medicine
Journal Abbreviation:Nat Med
Volume:15
Number:5
Page Range:545-552
Date:May 2009
Keywords:Blood Pressure, Homeostasis, Hypertension, Macrophages, Phagocytes, Vascular Endothelial Growth Factor Receptors, Signal Transduction, Skin, Skin Physiological Phenomena, Sodium Chloride, Dietary Sodium, Transcription Factors, Vascular Endothelial Growth Factor C, Animals, Mice
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.
ISSN:1078-8956
Publisher:Nature Publishing Group (U.S.A.)
Item Type:Article

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