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Immune cells control skin lymphatic electrolyte homeostasis and blood pressure

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Item Type:Article
Title:Immune cells control skin lymphatic electrolyte homeostasis and blood pressure
Creators Name:Wiig, H. and Schröder, A. and Neuhofer, W. and Jantsch, J. and Kopp, C. and Karlsen, T.V. and Boschmann, M. and Goss, J. and Bry, M. and Rakova, N. and Dahlmann, A. and Brenner, S. and Tenstad, O. and Nurmi, H. and Mervaala, E. and Wagner, H. and Beck, F.X. and Müller, D.N. and Kerjaschki, D. and Luft, F.C. and Harrison, D.G. and Alitalo, K. and Titze, J.
Abstract:The skin interstitium sequesters excess Na+ and Cl- in salt-sensitive hypertension. Mononuclear phagocyte system (MPS) cells are recruited to the skin, sense the hypertonic electrolyte accumulation in skin, and activate the tonicity-responsive enhancer-binding protein (TONEBP, also known as NFAT5) to initiate expression and secretion of VEGFC, which enhances electrolyte clearance via cutaneous lymph vessels and increases eNOS expression in blood vessels. It is unclear whether this local MPS response to osmotic stress is important to systemic blood pressure control. Herein, we show that deletion of TonEBP in mouse MPS cells prevents the VEGFC response to a high-salt diet (HSD) and increases blood pressure. Additionally, an antibody that blocks the lymph-endothelial VEGFC receptor, VEGFR3, selectively inhibited MPS-driven increases in cutaneous lymphatic capillary density, led to skin Cl- accumulation, and induced salt-sensitive hypertension. Mice overexpressing soluble VEGFR3 in epidermal keratinocytes exhibited hypoplastic cutaneous lymph capillaries and increased Na+, Cl-, and water retention in skin and salt-sensitive hypertension. Further, we found that HSD elevated skin osmolality above plasma levels. These results suggest that the skin contains a hypertonic interstitial fluid compartment in which MPS cells exert homeostatic and blood pressure-regulatory control by local organization of interstitial electrolyte clearance via TONEBP and VEGFC/VEGFR3-mediated modification of cutaneous lymphatic capillary function.
Keywords:Cultured Cells, Dietary Sodium Chloride, Homeostasis, Hyperplasia, Hypertension, Keratinocytes, Lymph, Lymphatic Vessels, Macrophages, Osmolar Concentration, Skin, Transcription Factors, Vascular Endothelial Growth Factor C, Vascular Endothelial Growth Factor Receptor-3, Water-Electrolyte Balance, Animals, Mice, Rats
Source:Journal of Clinical Investigation
Publisher:American Society for Clinical Investigation
Page Range:2803-2815
Date:1 July 2013
Official Publication:https://doi.org/10.1172/JCI60113
PubMed:View item in PubMed

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