Journal Article

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

Machura, Katharina, Luft, Friedrich C, Tammela, Tuomas, Ziomber, Agata, Dietsch, Peter, Wagner, Hubertus, Alitalo, Kari, Hilgers, Karl F, Goss, Jennifer, van Rooijen, Nico, Machnik, Agnes, Jantsch, Jonathan, Kurtz, Armin, Titze, Jens, Kerjaschki, Dontscho, Neuhofer, Wolfgang, Derer, Wolfgang, Müller, Dominik N, Beck, Franz-Xaver, Eckardt, Kai-Uwe, Dahlmann, Anke, Park, Joon-Keun

2009

Overview

Salt intake is associated with hypertension, but the mechanisms by which salt affects blood pressure remain unclear. Agnes Machnik et al . now show that mononuclear cells such as macrophages respond to dietary salt intake by producing the growth factor VEGF-C, leading to expansion of the lymphatic capillary network. Interference with this response in rats fed a high-salt diet exacerbates the increase in blood pressure caused by a high-salt diet pages 487–488 .. 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.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: Accumulation / Animals / Biomedical and Life Sciences / Biomedicine / Blood pressure / Blood Pressure - physiology / Cancer Research / Care and treatment / Cellular biology / Cellular signal transduction / Diet / Genetic aspects / Health aspects / Homeostasis / Hypertension / Hypertension - chemically induced / Hypertension - physiopathology / Immune system / Infectious Diseases / Leukocytes / Macrophages - physiology / Metabolic Diseases / Mice / Molecular Medicine / Neurosciences / Nitric oxide / Pathology / Phagocytes - drug effects / Phagocytes - physiology / Physiological aspects / Rats / Receptors, Vascular Endothelial Growth Factor - physiology / Retention / Risk factors / Salt / Salt-free diet / Salts / Signal Transduction / Skin - drug effects / Skin Physiological Phenomena / Sodium Chloride - adverse effects / Sodium, Dietary - adverse effects / Transcription Factors - physiology / Trapping / Vascular endothelial growth factor / Vascular Endothelial Growth Factor C - antagonists & inhibitors / Vascular Endothelial Growth Factor C - physiology