Blood pressure control is only skin deep


The lymphatic system is part of the circulatory system that transports immune cells to and from lymph nodes, absorbs fats from the digestive system, and removes the fluid surrounding cells (interstitial fluid) from tissues.  Under conditions of excess salt (sodium chloride) intake, the skin interstitium sequesters excess sodium and chloride molecules.  Sensing the accumulation of these ions, mononuclear phagocyte system (MPS) cells are recruited to the skin, where they increase the number of skin lymph capillaries to promote ion clearance. In the accompanying image, Helge Wiig and colleagues used whole mount staining of skin to track lymph capillary density from (left to right) mice fed a low salt,  high salt diet, or mice fed low or high salt diets and treated with a drug to disrupt MPS-driven changes in capillary density. These findings identify a role for MPS cells in blood pressure regulation via modification of the cutaneous lymph capillaries.  

Published June 3, 2013, by Jillian Hurst

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Immune cells control skin lymphatic electrolyte homeostasis and blood pressure
Helge Wiig, … , Kari Alitalo, Jens Titze
Helge Wiig, … , Kari Alitalo, Jens Titze
Published June 3, 2013
Citation Information: J Clin Invest. 2013;123(7):2803-2815. https://doi.org/10.1172/JCI60113.
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Research Article Immunology

Immune cells control skin lymphatic electrolyte homeostasis and blood pressure

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.

Authors

Helge Wiig, Agnes Schröder, Wolfgang Neuhofer, Jonathan Jantsch, Christoph Kopp, Tine V. Karlsen, Michael Boschmann, Jennifer Goss, Maija Bry, Natalia Rakova, Anke Dahlmann, Sven Brenner, Olav Tenstad, Harri Nurmi, Eero Mervaala, Hubertus Wagner, Franz-Xaver Beck, Dominik N. Müller, Dontscho Kerjaschki, Friedrich C. Luft, David G. Harrison, Kari Alitalo, Jens Titze

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