Constitutive smooth muscle tumour necrosis factor regulates microvascular myogenic responsiveness and systemic blood pressure

• Published in: Nature communications Vol. 8; no. 1; p. 14805
• Main Authors: Kroetsch, Jeffrey T., Levy, Andrew S., Zhang, Hangjun, Aschar-Sobbi, Roozbeh, Lidington, Darcy, Offermanns, Stefan, Nedospasov, Sergei A., Backx, Peter H., Heximer, Scott P., Bolz, Steffen-Sebastian
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 05.04.2017; Nature Publishing Group; Nature Portfolio
• Subjects: 13/106; 631/443/1338/1872; 631/443/1338/2729; 64/110; 64/60; 82/80; 96/95; Animals; Biology; Blood pressure; Blood Pressure - physiology; Dogs; Etanercept - pharmacology; Female; Heart failure; Heart Failure - prevention & control; Hemodynamics; Humanities and Social Sciences; Humans; Hypotheses; Immune system; Kinases; Male; Mesocricetus; Mice, Inbred C57BL; Mice, Knockout; Microcirculation; multidisciplinary; Muscle, Skeletal - metabolism; Muscle, Smooth, Vascular - metabolism; Musculoskeletal system; Science; Science (multidisciplinary); Signal Transduction - physiology; Smooth muscle; Species Specificity; Swine; Tumor Necrosis Factor-alpha - antagonists & inhibitors; Tumor Necrosis Factor-alpha - metabolism; Tumor Necrosis Factor-alpha - physiology; Tumor necrosis factor-TNF; Vasoconstriction; Veins & arteries; Toronto Ontario Canada; Canada; Germany
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/ncomms14805

Tumour necrosis factor (TNF) is a ubiquitously expressed cytokine with functions beyond the immune system. In several diseases, the induction of TNF expression in resistance artery smooth muscle cells enhances microvascular myogenic vasoconstriction and perturbs blood flow. This pathological role prompted our hypothesis that constitutively expressed TNF regulates myogenic signalling and systemic haemodynamics under non-pathological settings. Here we show that acutely deleting the TNF gene in smooth muscle cells or pharmacologically scavenging TNF with etanercept (ETN) reduces blood pressure and resistance artery myogenic responsiveness; the latter effect is conserved across five species, including humans. Changes in transmural pressure are transduced into intracellular signals by membrane-bound TNF (mTNF) that connect to a canonical myogenic signalling pathway. Our data positions mTNF ‘reverse signalling’ as an integral element of a microvascular mechanosensor; pathologic or therapeutic perturbations of TNF signalling, therefore, necessarily affect microvascular tone and systemic haemodynamics. TNF is typically viewed as an inflammatory mediator. Here the authors identify a non-inflammatory mechanism conserved across species whereby the constitutively expressed smooth muscle cell TNF mediates myogenic signal transduction in skeletal muscle resistance arteries and regulates mean arterial blood pressure.