title: 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.affiliation: Department of Biomedicine, University of Bergen, Bergen, Norway.
authors.forename: Helge
authors.initials: H
authors.lastname: Wiig
authors.forename: Agnes
authors.initials: A
authors.lastname: Schröder
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Neuhofer
authors.forename: Jonathan
authors.initials: J
authors.lastname: Jantsch
authors.forename: Christoph
authors.initials: C
authors.lastname: Kopp
authors.forename: Tine V
authors.initials: TV
authors.lastname: Karlsen
authors.forename: Michael
authors.initials: M
authors.lastname: Boschmann
authors.forename: Jennifer
authors.initials: J
authors.lastname: Goss
authors.forename: Maija
authors.initials: M
authors.lastname: Bry
authors.forename: Natalia
authors.initials: N
authors.lastname: Rakova
authors.forename: Anke
authors.initials: A
authors.lastname: Dahlmann
authors.forename: Sven
authors.initials: S
authors.lastname: Brenner
authors.forename: Olav
authors.initials: O
authors.lastname: Tenstad
authors.forename: Harri
authors.initials: H
authors.lastname: Nurmi
authors.forename: Eero
authors.initials: E
authors.lastname: Mervaala
authors.forename: Hubertus
authors.initials: H
authors.lastname: Wagner
authors.forename: Franz-Xaver
authors.initials: FX
authors.lastname: Beck
authors.forename: Dominik N
authors.initials: DN
authors.lastname: Müller
authors.forename: Dontscho
authors.initials: D
authors.lastname: Kerjaschki
authors.forename: Friedrich C
authors.initials: FC
authors.lastname: Luft
authors.forename: David G
authors.initials: DG
authors.lastname: Harrison
authors.forename: Kari
authors.initials: K
authors.lastname: Alitalo
authors.forename: Jens
authors.initials: J
authors.lastname: Titze
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D006706:Homeostasis; D006965:Hyperplasia / Q000378:metabolism; D006973:Hypertension / Q000276:immunology / Q000378:metabolism* / Q000503:physiopathology; D015603:Keratinocytes / Q000378:metabolism; D008196:Lymph / Q000378:metabolism*; D042601:Lymphatic Vessels / Q000503:physiopathology; D008264:Macrophages / Q000276:immunology; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D009994:Osmolar Concentration; D051381:Rats; D017207:Rats, Sprague-Dawley; D012867:Skin / Q000276:immunology / Q000378:metabolism*; D017673:Sodium Chloride, Dietary / Q000378:metabolism; D014157:Transcription Factors / Q000502:physiology; D042582:Vascular Endothelial Growth Factor C / Q000378:metabolism; D040321:Vascular Endothelial Growth Factor Receptor-3 / Q000037:antagonists & inhibitors / Q000378:metabolism; D014882:Water-Electrolyte Balance
chemical_list: C492200:Nfat5 protein, mouse; D017673:Sodium Chloride, Dietary; D014157:Transcription Factors; D042582:Vascular Endothelial Growth Factor C; C467483:vascular endothelial growth factor C, mouse; D040321:Vascular Endothelial Growth Factor Receptor-3